Many viruses have learned to evade or subvert the host antiviral immune responses by encoding and expressing immunomodulatory proteins that protect the virus from attack by elements of the innate and acquired immune systems. Some of these viral anti-immune regulators are expressed as secreted proteins that engage specific host immune targets in the extracellular environment, where they exhibit potent anti-immune properties. We review here viral immunomodulatory proteins that have been tested as anti-inflammatory reagents in animal models of disease caused by excessive inflammation or hyperactivated immune pathways. The potential for such viral molecules for the development of novel drugs to treat immune-based or inflammatory disorders is discussed.

Many viruses that successfully invade immunocompetent hosts do so by acquiring self-protective strategies to evade or subvert the consolidated forces of the innate and acquired immune responses. However, when viewed from the perspective of individual viruses faced with the challenge of surviving within specific host tissues, it is clear that each virus has acquired a unique portfolio of strategies to survive within the infected host. Thus, studies of individual viral anti-immune mechanisms tend to shed light on specific pathways that regulate the immune or inflammatory responses encountered by that particular virus. In contrast, an examination of viral strategies in general reveals that viruses as a whole can express effector molecules that target the entire gamut of immune pathways of vertebrate hosts, including some that likely remain to be uncovered. For example, a survey of the host antiviral response pathways already shown to be targeted by viruses reveals many of the key elements of modern immunology: Ag presentation, apoptosis, intracellular signaling, TLRs, cytokine pathways, serine proteinases, cytotoxic killing mechanisms, Ab generation, humoral regulators, and others. In fact, the growing collection of viral strategies that modulate these aspects of the immune system can be considered as comprising the discipline of anti-immunology and is the subject of a vast body of scientific literature (e.g., see Refs. 1, 2, 3, 4, 5, 6, 7, 8, 9 for some of the many excellent recent reviews).

The constant selection pressure from uncounted eons of coevolution between viruses and hosts has crafted virally derived anti-immune molecules of exquisite selectivity and potency. In many cases, viruses have evolved immunoregulators that no longer comply with the regulatory pressures of the host, thus endowing these molecules with highly specific anti-immune properties. Unlike the situation with commercial pharmaceuticals, viruses do not generally exploit immunomodulatory reagents that require high concentration to effectively perturb their intended immune pathways. Rather, viruses have evolved to express immunomodulators that are frequently delivered transiently at exceedingly low dosages (femtomolar to nanomolar) within a selected microenvironment of the infected tissues. Only rarely do viruses globally suppress immune responses of the host, and generally, this is only with viruses that replicate to very high titers in the blood or lymphatic system (10, 11, 12, 13). In fact, the specific virus-encoded immunomodulators that have been examined to date require extremely low treatment dosages to regulate their target immune or inflammatory pathways without inducing generalized immunosuppression or promoting supervening infections. This combination of high potency and highly specific biochemical targeting provides a powerful platform with which to develop next-generation drugs based on viral protein immunomodulators to treat diseases based on excessive inflammation or hyperactive immune reactions (14, 15, 16, 17, 18, 19).

In this review, we focus on virus-encoded immunoregulators that are secreted from infected cells and target specific pathways that regulate host immune or inflammatory responses (Fig. 1). In particular, we discuss in greater depth those virus-encoded immunomodulators that have been tested individually, in the absence of virus infection, and examined as therapeutic reagents in models of diseases associated with excessive inflammatory or immune responses (Table I). Finally, we consider the technical and regulatory challenges of using virus-derived proteins with anti-inflammatory or anti-immune properties for treatment of human diseases, and the prospects for mining the virus ecosphere for future immunomodulatory candidates.

FIGURE 1.

Major classes of virus-encoded secreted immunomodulators.

FIGURE 1.

Major classes of virus-encoded secreted immunomodulators.

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Table I.

Treatment of inflammatory disease models with immunomodulatory viral proteinsa

ClassProtein (Virus)TypeDisease ModelReferences
Cytokine inhibitors M-T7 (myxoma) CBP (type I) Vascular hyperplasia (rat, rabbit) 53  
   Renal and aortic allograft vasculopathy (rat) 5455  
 35k/vCCI (cowpox, vaccina) CBP (type II) Skin inflammation (guinea pig) 40  
   Airway inflammation (mouse) 56  
   Peritoneal inflammation (mouse) 57  
 M-T1 (myxoma)  Aortic allograft vasculopathy (rat) 55  
 M3 (γ-68 herpesvirus) CBP (type III) Pancreatic and vascular inflammation (mouse) 5859  
   Aortic allograft vasculopathy (rat) 55  
Cytokine mimics vMIP-II (KSHV) Chemokine homolog Glomerulonephritis (rat) 74  
   Cardiac allograft (mouse) 66  
   Spinal cord injury (rat) 73  
   Cerebral ischemia (mouse, rat) 7172  
   DTH responses (mouse) 75  
 MC148 (MCV) Chemokine homolog Cardiac allograft (mouse) 66  
 vIL-10 (EBV) IL-10 homolog Tumor rejection (mouse) 79  
   Allograft rejection (rat, mouse) 909293949596979899100101102103104  
   Arthritis (mouse, SCID mouse, rabbit) 808182838485888991  
   Pathogen responses (mouse) 115  
   Venous thrombosis (rat, mouse) 107108  
   DTH responses (mouse) 112113  
   Sepsis (mouse) 114  
   Diabetes (NOD mouse) 109110  
   Osteolysis (mouse) 8586  
   Autoimmune ocular disease (mouse, rat, rabbits) 87105106  
   Particle inflammation (mouse) 116  
   Glomerulonephritis (rat) 111  
Complement inhibitor VCP (vaccinia) Complement inhibitor Xenograft rejection (mouse, rat, guinea pig) 128131132134138  
   Neurotrauma and spinal cord injury (rat) 140141142  
   Complement inhibition (baboon) 133  
   Peritonitis (mouse) 130  
Inflammatory cell inhibitor SERP-I (myxoma) Serpin Injury vasculopathy (rabbit, mouse, rat, rooster, pig) 154155156  
   Rheumatoid arthritis (rabbit) 161  
   Allograft vasculopathy (rat) 158159160  
ClassProtein (Virus)TypeDisease ModelReferences
Cytokine inhibitors M-T7 (myxoma) CBP (type I) Vascular hyperplasia (rat, rabbit) 53  
   Renal and aortic allograft vasculopathy (rat) 5455  
 35k/vCCI (cowpox, vaccina) CBP (type II) Skin inflammation (guinea pig) 40  
   Airway inflammation (mouse) 56  
   Peritoneal inflammation (mouse) 57  
 M-T1 (myxoma)  Aortic allograft vasculopathy (rat) 55  
 M3 (γ-68 herpesvirus) CBP (type III) Pancreatic and vascular inflammation (mouse) 5859  
   Aortic allograft vasculopathy (rat) 55  
Cytokine mimics vMIP-II (KSHV) Chemokine homolog Glomerulonephritis (rat) 74  
   Cardiac allograft (mouse) 66  
   Spinal cord injury (rat) 73  
   Cerebral ischemia (mouse, rat) 7172  
   DTH responses (mouse) 75  
 MC148 (MCV) Chemokine homolog Cardiac allograft (mouse) 66  
 vIL-10 (EBV) IL-10 homolog Tumor rejection (mouse) 79  
   Allograft rejection (rat, mouse) 909293949596979899100101102103104  
   Arthritis (mouse, SCID mouse, rabbit) 808182838485888991  
   Pathogen responses (mouse) 115  
   Venous thrombosis (rat, mouse) 107108  
   DTH responses (mouse) 112113  
   Sepsis (mouse) 114  
   Diabetes (NOD mouse) 109110  
   Osteolysis (mouse) 8586  
   Autoimmune ocular disease (mouse, rat, rabbits) 87105106  
   Particle inflammation (mouse) 116  
   Glomerulonephritis (rat) 111  
Complement inhibitor VCP (vaccinia) Complement inhibitor Xenograft rejection (mouse, rat, guinea pig) 128131132134138  
   Neurotrauma and spinal cord injury (rat) 140141142  
   Complement inhibition (baboon) 133  
   Peritonitis (mouse) 130  
Inflammatory cell inhibitor SERP-I (myxoma) Serpin Injury vasculopathy (rabbit, mouse, rat, rooster, pig) 154155156  
   Rheumatoid arthritis (rabbit) 161  
   Allograft vasculopathy (rat) 158159160  
a

KSHV, Kaposi’s sarcoma herpesvirus; DTH, delayed-type hypersensitivity.

Virus-encoded immunomodulatory proteins have been identified from a wide variety of virus families, but by far the largest number come from the DNA viruses with large genomes that can express multiple genes beyond those minimally required for virus replication and propagation in tissue culture. Of these, members of the poxvirus and herpesvirus families have evolved to encode more such immunomodulators than all other virus families combined (1, 9, 14, 15, 16, 17, 18, 19). In some cases, the origins of these viral genes are clearly rooted in the piracy of known host immune genes, likely by recombination with reverse-transcribed cDNA versions of expressed host genes from ancestrally infected host organisms. Presumably, any selective advantage of such host-derived genes would be manifested by increased survival of the newly recombined virus in the infected host. However, following acquisition of a host-derived immunomodulator by a given virus, subsequent evolutionary pressures can result in alterations of biologic functions of the captured modulator that are advantageous to the virus (20, 21, 22). Thus, progressive loss of modulatory functions that disfavor virus propagation can also be coupled with the acquisition of progressively increased inhibitory properties that promote virus survival, thereby allowing the virus to circumvent the host-mediated regulatory activities. As an example, the viral (v)4 IL-10 gene of EBV (BCRF1) exhibits significant sequence homology to the cDNA version of human IL-10, suggesting recent acquisition from infected humans or another closely related mammalian host (23). However, the current viral version of this cytokine has lost many of the immunostimulatory properties associated with the host ligand while retaining its immunosuppressive features (23, 24, 25).

The second, and more evolutionarily mysterious, class of viral immunomodulators exhibit no obvious sequence relationship to any known host molecules. These so-called orphan viral regulators have usually been discovered empirically by the ability to bind and inhibit specific host ligands. For example, the four classes of viral chemokine-binding proteins (CBPs) were all discovered by binding and inhibition studies with known host chemokines, rather than by any sequence relationship with known immune genes (9, 14, 15, 18, 26, 27, 28, 29). For these viral regulators, it is difficult to assess whether they represent examples of independent convergent evolution or whether their true relationship to host-derived genes will become revealed only as more genomic information from other organisms becomes available. It is also entirely plausible that some of these unique viral genes were originally derived from ancient host species that are now extinct, and their progenitor host genes may never be accurately documented.

Virus-encoded immunomodulators can function from a variety of cellular and tissue locations. For example, they can be expressed intracellularly within the infected cell, function at the surface of infected cells or virion particles, or be secreted into the extracellular environment. This review will focus on the secreted immunoregulators that have been independently expressed and used to treat disorders in animal models of inflammatory diseases. These secreted immunomodulators have been subdivided into virokines (ligand-like) or viroceptors (receptor-like), but note that this thematic distinction is somewhat arbitrary, because many viral regulators were identified operationally as binding proteins or inhibitors of known immune pathways, and function by still-undefined mechanisms (30, 31, 32, 33). In any event, only a small fraction of the currently known immunoregulators from viruses have ever been tested as anti-inflammatory or anti-immune reagents in animal models (Table I), and these are the specific examples considered in greater detail in the following sections.

Virus-encoded cytokine inhibitors generally function as soluble receptor mimics or as secreted cytokine-binding proteins to scavenge the targeted ligand away from host receptors at the surface of immune cells. In the case of viral CBPs, four distinct protein classes of such inhibitors (termed types I to IV) have been discovered on the basis of physical chemokine-binding and inhibition assays (9, 18, 26, 27, 28, 29, 30). Each of these four types of CBP represent a distinctly unique protein class, and the crystal structures of two members (types II and III) reveal domain folds unrelated to any known host immune molecule (34, 35, 36). Type I CBP is represented by a single member, M-T7 from myxoma virus, a poxvirus viroceptor originally identified as a secreted 37-kDa inhibitor specific for rabbit IFN-γ but later shown to bind with low affinity to the glycosaminoglycan (GAG) domain of a broad spectrum of C/CC/CXC chemokines and inhibit leukocyte taxis in virus-infected tissues (37, 38, 39). Type II CBPs, also called viral CC chemokine inhibitors (vCCIs), have been isolated from several poxviruses (e.g., myxoma, certain vaccinia strains, rabbitpox, and cowpox) and shown to specifically bind with high affinity and inhibit a broad spectrum of CC chemokines (40, 41, 42, 43). Type III CPB is exemplified by the M3 protein of γ-68 herpesvirus, which binds and inhibits members of all known classes of chemokines and blocks chemokine interactions with both their receptors and GAG elements responsible for chemokine gradients (35, 44, 45, 46, 47, 48). The type IV CBPs were only recently discovered in several α-herpesviruses, when it was shown that particular isoforms of gpG possess the ability to bind and inhibit a wide spectrum of C/CC/CXC chemokines (49). Overall, there is considerable interest in the development of novel chemokine-modulatory drugs, and the known viral CBPs represent a potent repository of reagents with which to manipulate chemokine functions and leukocyte trafficking (50, 51, 52).

The viral CBPs tested to date in animal models have each demonstrated clearly the elegant sophistication that viruses have evolved to thwart mammalian immune defenses. Multiple studies with CBPs I–III have consistently demonstrated effective inhibition of inflammatory disorders in a range of animal disease models. M-T7, or the type I CBP, was found to block early invasion of macrophages and T lymphocytes at sites of vascular injury in rat and rabbit models (53, 54, 55). Infusion of purified M-T7 protein resulted in the inhibition of early mononuclear cell invasion postinjury and was associated with long-term reductions in atherosclerotic plaque growth (vasculopathy) after either transplant or balloon angioplasty injury (53, 54, 55). The lack of species specificity of M-T7 in a variety of animal models suggests that the inhibition of cell invasion and plaque growth was in fact the result of targeting the host chemokine circuitry rather than IFN-γ, whose inhibition by M-T7 is restricted to the rabbit species (53, 54, 55, 181). Furthermore, M-T7 protein was clinically efficacious in suppressing the vascular pathology associated with these various models even when given transiently at very low dosages (picograms to nanograms per kilogram of body weight). For example, Bedard et al. (54) demonstrated that i.v. treatment with M-T7 protein, given daily at doses up to 80 ng/kg for only the first 10 days posttransplant, markedly reduced vasculopathy and organ scarring in rat renal transplants even at 5 mo after surgery.

The viral CBP type II, M-T1 from myxoma virus, which shares close homology to the vCCI/35k from vaccinia, has also been tested in rat and mouse aortic allograft models. In the rat model, M-T1 protein (given i.v. as a single protein bolus administered immediately following vascular transplant) mediated blockade of early mononuclear cell invasion and the late development of chronic transplant vasculopathy (55). Dabbagh et al. (56) demonstrated that administration of vCCI/35k as an Fc fusion protein significantly reduced airway inflammation in a mouse model. vCCI/35k also reduced eosinophil invasion associated with eotaxin-mediated inflammation in guinea pigs (40, 55). Finally, when expressed from an adenovirus vector that was delivered by i.p. injection, vCCI/35k also reduced inflammatory cell recruitment induced by biogel in peritoneal exudates in mice (57). Like the type I and II viral CBPs, M3, a panchemokine class inhibitor, also displayed potent therapeutic activity, blocking aortic allograft vasculopathy (55) and pancreatic inflammation (58). Significantly, endogenous M3 expression from transgenic mice also blocks intimal hyperplasia (59).

The analysis of these three diverse classes of viral CBPs reaffirm the importance and impact of the chemokine system on early inflammatory responses to trauma and on long-term disease development. Whether the CBPs were administered as purified proteins (53, 54, 55, 56), expressed through adenoviral vectors (57), or produced endogenously in transgenic mice (58), profound inhibition of inflammation was consistently observed. Although CBPs provide powerful tools to deconstruct the critical roles that chemokines play during inflammatory responses, the actual mechanisms through which these viral CBPs functionally block chemokine responses when given in such relatively low doses for very restricted time frames still require further studies. For example, the CBP type I, M-T7, inhibits inflammatory influx effectively in vivo at very low dosages (53, 54, 55), whereas this protein binds the GAG binding domain of chemokines with only low affinity in vitro (37). One clue to this paradoxical result may lie in the fact that the low-affinity GAG-binding domain of many chemokines is critical for gradient stabilization and ligand presentation to the influxing leukocytes (60, 61, 62). In any event, this is a clear example of where further studies with the viral modulator will likely shed new light on cellular chemokine-mediated response pathways in general.

In the previous section, the case of CBPs as anti-inflammatory reagents was considered, and here, we review virus-encoded mimics of known chemokines or cytokines. Of the many known examples of such immune ligand mimicry, the viral homologs of chemokines and IL-10 are the only examples, to date, that have been tested in animal models of disease. In the case of viral chemokine mimics, the two examples are MC148 of Molluscum contagiosum virus (MCV) and vMIP-II of human herpesvirus 8/Kaposi’s sarcoma herpesvirus. MC148 of MCV specifically binds human CCR8 and antagonizes the lone host chemokine ligand that signals via this receptor (I-309), whereas vMIP-II is both an agonist for CCR3 and a promiscuous antagonist for at least 10 human CC and CXC chemokine receptors (63, 64, 65). Unlike vMIP-II, MC148 does not recognize any known murine chemokine receptors, and thus is not predicted to be anti-inflammatory in mouse models, but the available data indicate that both viral ligands can nevertheless prolong cardiac allograft survival in mice (66). vMIP-II also possesses the unique ability to block Th1-polarized T lymphocytes while stimulating Th2 responses, thereby disfavoring cell-mediated immune responses (67). At present, it is not understood how MC148 acts in the murine system, but it is possible that it also targets inflammatory pathways independent of the chemokine system, or there are other still-to-be identified chemokine receptors on primary cells that are antagonized by MC148 (68).

Chemokines are expressed at elevated concentrations in the brain after mechanical trauma or chronic neuropathies such as Alzheimer’s disease and multiple sclerosis (69, 70, 71). Takami et al. (72) have demonstrated that intracerebroventricular injections of purified vMIP-II protein, which can antagonize MIP-1α (or CCL3), reduced infarct size at 48 h after middle cerebral arterial occlusion, whereas, conversely, injection of MIP-1α increased infarct size in mice. Ghirnikar et al. (73) similarly found that infusion of vMIP-II protein for 7 days via osmotic minipump brain infusion after spinal cord contusion in rats decreased the number of infiltrating neutrophils (day 1 postinjury), macrophages (days 3–7 postinjury), and microglia (days 3–7 postinjury). The reduction in inflammatory cell invasion was associated with reduced neuronal loss and increased expression of Bcl-2, an endogenous apoptosis inhibitor (73). In a rat model of glomerulonephritis, i.v. infusion of vMIP-II protein inhibited CC and CX3C chemokine expression, macrophage and T lymphocyte invasion, crescentic glomeruli, and proteinuria (protein loss in the urine indicative of kidney damage) (74). Inflammatory exudates, which are believed to produce some of the CD8+ T cell-mediated immunopathology associated with lymphocytic choriomeningitis virus infections, were also reduced with vMIP-II treatment in mice (75). In a cardiac allograft transplant model in mice, gene transfer of vMIP-II and MC148 reduced CTL infiltrates and alloantibody production with associated prolonged graft survival (survival for 21 days with vMIP-II vs 13 days for control) (66). Injection of vIL-10 together with vMIP-II further enhanced graft survival, suggesting these viral immunomodulating cytokines inhibited inflammatory responses through synergistic pathways (66).

The second class of cytokine mimicry considered here is vIL-10 from EBV, which exhibits 83% identity to the human IL-10 (23, 24, 25). Despite this sequence similarity, vIL-10 exhibits primarily the immune-inhibitory properties associated with the cellular ligand (e.g., suppression of Th1-polarized responses and monocyte inhibition) and has apparently lost the immunostimulatory features normally associated with host IL-10 (e.g., activation of dendritic cells, NK cells, and some T cells) (76, 77, 78, 79). This exacerbated inhibitory aspect of vIL-10 makes it an attractive therapeutic candidate for tolerance induction following allografts or for immunosuppression to treat disease pathologies driven by inappropriately activated lymphocytes. vIL-10 gene delivery has to date been widely tested in animal models of arthritis, allograft transplantation, osteolysis, glomerulonephritis, diabetes, uveoretinitis, venous thrombosis, and systemic inflammation associated with infection and sepsis (Table I). A reduction in proinflammatory cytokines (IL-1, IL-6, and TNF-α, among others) and a conversion from Th1 to Th2 lymphocyte response was associated with suppression of inflammation in many of the animal models tested. The extensive testing of vIL-10 in a wide range of animal models, and the large numbers of laboratories that have demonstrated effective repression of disease states in these models, strongly supports the concept that vIL-10 may provide an effective therapeutic approach to suppression of both inflammation-based and autoimmune-based disorders.

Adenovirus or adeno-associated virus delivery of the vIL-10 gene has been demonstrated to reduce Ag-induced joint inflammation in rabbits (80), mouse models of arthritis (81, 82, 83, 84), and wear debris-initiated inflammation and osteoclastogenesis (osteolysis in joint replacements) (85, 86). The mouse model of Sjogren-like syndrome, featuring reduced tear production and ocular surface disease (autoimmune dacryoadenitis), is notable in that vIL-10 suppressed pathologic responses for a common autoimmune disorder for which few, if any, therapies are currently available (87). vIL-10 gene delivery also prevented transplanted human rheumatoid synovial tissue invasion into cartilage in SCID mice (88), indicating effective blockade of human inflammatory tissue-mediated in-joint destruction. When the gene for soluble TNFR was delivered to mice in conjunction with vIL-10, there was a greater synergistic reduction in joint inflammation (89). vIL-10 treatment induced a Th2 phenotype and was variously found to reduce the expression of IL-1, IL-2, IL-6, TNF-α, cyclooxygenase 2, and matrix metalloproteinase 3, and to increase tissue inhibitor of matrix metalloproteinase-1 (88, 89, 90). Of interest, vIL-10 suppression was transferred to contralateral untreated joints through an Ag-dependent mechanism (91).

Gene delivery of vIL-10 by retrovirus, plasmid-based gene transfer, adenovirus, or liposomes has also been shown to increase allograft survival after solid organ heart, kidney, and hepatic transplants in mice (92, 93, 94, 95, 96) and rats (97, 98, 99, 100). vIL-10 has also been found in an immunosuppressed patient post-renal transplantation and was associated with preserved renal allograft function (101). vIL-10-mediated prolongation of graft survival was associated with a switch from Th1 to Th2 responses and impairing APC function with associated induction of tolerance (93, 102). Together with the altered Th2/Th1 response ratio, a reduction in costimulatory molecules (B7.1 and B7.2), cytokines (IL-2, IL-4, murine IL-10, and IFN-γ), and inducible NO synthase was detected in several models (92). Although a shift from Th1 to Th2 responses was detected, true tolerance was not seen, as evidenced by the acute rejection of both the first and second grafts, following implant of a second heart transplant into mice that had previously received a cardiac transplant with vIL-10 gene therapy (93). T lymphocyte allostimulatory activity of mouse dendritic cells and dendritic cell maturation was reduced in mouse studies of mixed lymphocyte responses in vitro (102). Conversely, vIL-10 expression from transplanted transgenic mouse hearts did not suppress graft rejection (103), whereas pretreatment of donor rat hearts with adenovirus-expressed vIL-10 did prolong graft survival (97). However, in subsequent work, expression from autologous hemopoietic stem cells did prolong allograft survival, and concomitant cyclosporin A treatment enhanced vIL-10-mediated graft survival (92, 97, 104).

vIL-10 has also been tested in animal models of autoimmune dacroadenitis and uveoretinitis (87, 105, 106), venous thrombosis (107, 108), autoimmune diabetes (109, 110), glomerulonephritis (111), delayed-type hypersensitivity (112, 113), and sepsis (114). vIL-10 significantly improved survival and reductions in pancreas and liver injury in the mouse models of sepsis induced by Saccharomyces cerevisiae particles or with choline-deficient diets (114). Conversely, in parasitic infection with Schistosoma mansoni, vIL-10 had no effect on the infestation, whereas with Leishmania amazonensis infestation, vIL-10 treatment led to an initial decrease in lesions followed by a later exacerbation (115). In the murine air pouch model of particle-induced inflammation, vIL-10 gene therapy decreased proinflammatory cytokine responses with reduction in IL-1α, IL-6, and TNF-α, with associated reductions in macrophage response and invasion (116).

The regulation of complement activation at sites of inflammation is under tight control, and some viruses have specifically captured host regulatory components designed to limit complement attack of virus-infected cells (117, 118, 119, 120). In particular, the poxviruses and herpesviruses have acquired and adapted a number of key host-derived inhibitors of the complement cascade to blunt the early stages of complement-mediated responses in infected tissues (121, 122, 123). The 35-kDa secreted inhibitor of complement expressed by some strains of vaccinia virus was, in fact, the first such viral complement regulator discovered (124, 125, 126). The vaccinia complement control protein (VCP) and the closely related version from cowpox virus, designated inflammatory modulatory protein (IMP), have been shown to structurally resemble host C4b-binding protein and to be capable of binding cellular regulators like C4b or C3b and heparin simultaneously (127). VCP and IMP have been proposed to be capable of blocking the interaction between chemokines and GAGs to inhibit chemokine gradient formation and leukocyte chemotaxis, but this particular activity remains to be demonstrated in vivo (128). Purified VCP blocks complement activation at several stages and has been proposed to be a good candidate for the treatment of Alzheimer’s disease, multiple organ dysfunction syndrome, peritonitis, and xenograft rejection (129, 130).

VCP has been tested in animal models and has shown promise for treating hyperacute rejection following xenotransplantation (131, 132, 133, 134). Complement responses, both through the classical and alternate pathways, mediate hyperacute rejection, which markedly limits the potential for xenotransplantation (135). Chronic organ shortages have led to intensive investigations into methods that would allow for the use of alternate organ sources, such as pigs, for human transplants, and prevention of complement activation has been shown to reduce hyperacute rejection reactions (136, 137). Anderson et al. (128, 131) have demonstrated that treatment with purified VCP prolonged survival time 10-fold for xenotransplanted hearts using a heterotopic cervical mouse heart to sensitized rat transplant model. VCP treatment also inhibited xenoantibody binding to MHC class I molecules on endothelial cells and activation of the complement pathway (128). As well, VCP blocked human galactose-α-1,3-galactose Ab binding sites on pig endothelial cells, complement activation, and NK cell-mediated endothelial cell lysis (138). The cowpoxviral IMP also blocked inflammatory cell responses in mouse dermal pouch and footpad models (139).

Finally, VCP has shown promise for treatment in animal models of injury to the CNS (neurotrauma) (140, 141, 142). Interestingly, not only full-length VCP, but also a truncated version of VCP that lacks complement inhibitory properties but retains the ability to bind heparin, still provides neuroprotection, strongly suggesting multiple activities for this viral immunomodulatory protein (141).

Serpins form a large superfamily of regulatory proteins that orchestrate key pathways such as blood coagulation, fibrinolysis, complement activation, humoral responses, embryonic development, apoptosis, and inflammation (143, 144, 145, 146). Serpins represent from 3 to 10% of circulating plasma proteins, and are suspected to have central roles in regulating the innate inflammatory responses to viruses and tissue trauma. To date, poxviruses are the only viruses known to encode biologically active serpins, and these viral serpins can be detected in either the intracellular or extracellular compartments (147, 148). The only well-characterized secreted viral serpin is Serp-1, encoded by myxoma virus, which is expressed as a 55-kDa secreted glycoprotein that binds and inhibits several human host serine proteinases such as urokinase-type and tissue-type plasminogen activators, and plasmin (149, 150, 151). When the Serp-1 gene was deleted from myxoma virus, the resulting knockout virus was attenuated and unable to block attack and clearance by responsive inflammatory cells (152, 153). Given this potential as a potent anti-inflammatory reagent, Serp-1 was the first viral immunomodulatory protein to be purified and tested as an anti-inflammatory reagent in an animal model of inflammation (154, 155).

Studies in rabbit, rat, rooster, and swine models all revealed marked effectiveness of Serp-1 protein at reducing mononuclear cell/macrophage invasion into sites of arterial trauma, after a single picogram-to-nanogram dose given either locally into the arterial wall or systemically by i.v. injection (155, 156). Under conditions of acute infusion, Serp-1 protein behaves with pharmacokinetics that resemble other nonviral protein pharmaceuticals (157). After 4 wk, atherosclerotic plaque growth was markedly reduced in these models, indicating that even short-term Serp-1 protein dosing at the time of vascular injury can reduce longer term vasculopathy associated with chronic disease progression. Subsequent work in ApoE-deficient mice demonstrated a significant reduction in plaque growth after carotid cuff compression injury and an associated reduction in macrophage invasion, suggesting that Serp-1 treatment stabilized the arterial wall in this mouse model (158). Effective reductions in plaque growth were also observed after 4 wk in rat aortic allografts following acute treatment with Serp-1 right at the time of transplant (159). Further work in heart transplant models (rat) have also demonstrated that transient Serp-1-induced reductions in early monocyte/macrophage invasions were associated with long-term decreases in graft vasculopathy when coupled with continuous cyclosporin A dosing to inhibit T cell allograft responses (160). In keeping with the adoptive evolution of viral serpins to a uniquely inhibitory function, Serp-1 was found to block inflammatory responses and plaque growth in mouse models via the cellular urokinase-type plasminogen activator receptor, a receptor targeted by the mammalian antithrombolytic serpin, plasminogen activator inhibitor-1 (161). Finally, Serp-1 treatment has also been shown to reduce the levels of chronic inflammation in the rabbit model of Ag-induced arthritis (162).

Taken together, all of these studies reinforce the conclusion that even transient dosing with Serp-1 can reduce the magnitude of monocyte/macrophage responses to proinflammatory stimuli, and thereby mitigate the subsequent pathophysiological consequences of chronic low-level inflammation that invariably accompanies physical trauma and disease states as diverse as transplantation, angioplasty, or rheumatoid arthritis.

All therapeutic proteins currently licensed for use in humans, whether from human or nonhuman sources, exhibit some degree of immunogenicity in patients (163, 164, 165, 166, 167, 168, 169). The resulting Abs that are induced in susceptible patients are sometimes neutralizing but more frequently compromise the protein half-life, and only in rare cases do such induced Abs become deleterious to the patient, for example by inactivating a critical endogenous host protein such as erythropoietin (170, 171, 172, 173). Foreign nonhuman proteins, such as bacterial streptokinase/staphylokinase, bovine adenosine deaminase, or salmon calcitonin, have been used transiently for acute therapeutic indications, but even fully human-derived recombinant proteins, such as human insulin, can be limited for long-term chronic administration protocols because of immunogenicity (166, 167, 168). As a consequence, many experimental strategies have been investigated to reduce the immunogenicity of protein pharmaceuticals, such as PEGylation, glycosylation, epitope removal, humanization, and tolerization (166, 167, 168, 169, 170, 174). Also, note that some clinical treatment regimens specifically induce immunosuppression, for example, cyclosporine for allograft transplantation or methotrexate for rheumatoid arthritis, which mitigates the immunogenic responses to any coadministered protein-based pharmaceuticals (166, 167, 168, 169, 174). Thus, such treatment regimens might allow for even chronic coadministration of viral immunomodulatory proteins with synergistic anti-inflammatory properties.

In the case of viral proteins with potent immunomodulatory or anti-inflammatory properties, the question of whether immunogenicity in humans will restrict their usage to only acute clinical indications will be properly addressed only by carefully designed human phase I and II trials, in part because of the poor prognostic capacity of animal-based immunogenicity studies (175, 176). For all biopharmaceuticals, the precise extent of immunogenicity of any given protein product will depend upon a spectrum of parameters, the most significant of which are the following: product purity, formulation, injection route, dosage, frequency of administration (i.e., acute vs chronic), and immune status of the patient population (166, 167, 168). The three principal clinical effects of concern that need to be addressed before viral proteins would be licensed for human use are, first, allergic reactions; second, the effects of any Abs to the therapeutic that could lead to treatment resistance (i.e., neutralization or changes in pharmacokinetics); and third, potential autoimmune responses induced by cross-reactive Abs against related endogenous human proteins. In fact, these concerns are equally applicable to protein biopharmaceuticals of either human or nonhuman origin, and require detailed analysis in human trials for quantification of induced Ab levels, cross-reactive profiles of any induced Abs, and efficacy parameters following multiple treatment protocols (164, 165, 168, 169, 175). Thus, the potential immunogenicity of viral protein-based biotherapeutics can be accurately evaluated only at the clinical trial level on a case-by-case basis.

As talented students of the mammalian immune system, viruses have developed an extraordinary range of virally mediated immunomodulatory agents. Through the unraveling of discoveries made by viruses, a new class of therapeutic agents has been revealed based upon virus-engineered immunomodulatory proteins. Viruses were the first organisms for which complete genome sequences were deduced, beginning a quarter of a century ago, and the science of “virogenomics” has been expanding rapidly ever since (177, 178, 179). The repertoire of novel viral gene products that are devoted to host modulation has also been proliferating at an astounding rate, and there are reasons to suspect that we have uncovered only the tip of the virus iceberg. For example, the discipline of virology has largely focused on viruses that cause overt pathogenesis, but the viral ecosphere is populated largely by apathogenic members that still remain to be discovered. Indeed, there are proposals to fully define the complete human “virome,” or the summated sequences of all viruses that are present in the human population (180), and such genomic mining will likely uncover an even greater armamentarium of viral immunoregulators.

In some ways, the area of viral biotherapeutics mirrors the situation with snake venom peptides, which provided the basis for the development of two key classes of pharmaceuticals, angiotensin-converting enzyme inhibitors and gpIIbIIIa antagonists, which are widely used to reduce symptoms and prolong life in cardiovascular disease. In a similar fashion, we project that immunomodulatory viral proteins will establish a new pharmacopoeia for treatment of inflammation-based disorders. As more is learned about how these virus-derived drug candidates behave as pharmacological reagents, particularly in human clinical trials, we will be in better position to evaluate which human diseases have the potential to be effectively treated with this novel class of biopharmaceuticals.

We thank John Barrett and Colin Macauley for helpful comments, and Doris Hall for assistance with the manuscript preparation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

G.M. holds a Canada Research Chair in Molecular Virology. The laboratories of A.L. and G.M. are funded by the Canadian Institutes for Health Research, National Cancer Institute of Canada, and the Heart and Stroke Foundation.

2

A.L. and G.M. are cofounders of Viron Therapeutics, which is developing viral proteins as anti-inflammatory therapeutics.

4

Abbreviations used in this paper: v, viral; CBP, chemokine-binding protein; GAG, glycosaminoglycan; MCV, Molluscum contagiosum virus; vCCI, viral CC chemokine inhibitor; VCP, vaccinia complement control protein; IMP, inflammatory modulatory protein; serpin, serine proteinase inhibitor.

1
Alcamí, A., U. H. Koszinowski.
2000
. Viral mechanisms of immune evasion.
Immunol. Today
21
:
447
.
2
Tortorella, D., B. E. Gewurz, M. H. Furman, D. J. Schust, H. L. Ploegh.
2000
. Viral subversion of the immune system.
Annu. Rev. Immunol.
18
:
861
.
3
Agrawal, N., H. Korkaya, S. Jameel.
2000
. How viruses evade host responses.
Curr. Sci.
79
:
711
.
4
Xu, X.-N., G. R. Screaton, A. J. McMichael.
2001
. Virus infections: escape resistance, and counterattack.
Immunity
15
:
867
.
5
Lorenzo, M. E., H. L. Ploegh, R. S. Tirabassi.
2001
. Viral immune evasion strategies and the underlying cell biology.
Immunology
13
:
1
.
6
Gewurz, B. E., R. Gaudet, D. Tortorella, E. W. Wang, H. L. Ploegh.
2001
. Virus subversion of immunity: a structural perspective.
Curr. Opin. Immunol.
13
:
442
.
7
Vossen, M. T. M., E. M. Westerhout, C. Soderberg-Naucler, E. J. H. J. Wiertz.
2002
. Viral immune evasion: a masterpiece of evolution.
Immunogenetics
54
:
527
.
8
Petersen, J. L., C. R. Morris, J. C. Solheim.
2003
. Virus evasion of MHC class I molecule presentation.
J. Immunol.
171
:
4473
.
9
Alcami, A..
2003
. Viral mimicry of cytokines, chemokines and their receptors.
Nat. Rev. Immunol.
3
:
36
.
10
Piguet, V., D. Trono.
2001
. Living in oblivion: HIV immune evasion.
Immunology
13
:
51
.
11
Johnson, W. E., R. C. Desrosiers.
2002
. Viral persistence: HIV’s strategies of immune system evasion.
Annu. Rev. Med.
53
:
499
.
12
Woolhouse, M. E. J., J. P. Webster, E. Domingo, B. Charlesworth, B. R. Levin.
2002
. Biological and biomedical implications of the co-evolution of pathogens and their hosts.
Nat. Genet.
32
:
569
.
13
Naniche, D., M. B. A. Oldstone.
2000
. Generalized immunosuppression: how viruses undermine the immune response.
Cell. Mol. Life Sci.
57
:
1399
.
14
McFadden, G., P. M. Murphy.
2000
. Host-related immunomodulators encoded by poxviruses and herpesviruses.
Curr. Opin. Microbiol.
3
:
371
.
15
Smith, G. L..
2000
. Secreted poxvirus proteins that interact with the immune system. M. W. Cunningham, and R. S. Fujinami, eds.
Effects of Microbes on the Immune System
491
. Lippincott Williams & Wilkins, Philadelphia.
16
Moss, B., J. L. Shisler.
2001
. Immunology 101 at poxvirus U: immune evasion genes.
Semin. Immunol.
13
:
59
.
17
Johnston, J. B., G. McFadden.
2003
. Poxvirus immunomodulatory strategies: current perspectives.
J. Virol.
77
:
6093
.
18
Seet, B. T., J. B. Johnston, C. R. Brunetti, J. W. Barrett, H. Everett, C. Cameron, J. Sypula, S. H. Nazarian, A. Lucas, G. McFadden.
2003
. Poxviruses and immune evasion.
Annu. Rev. Immunol.
21
:
377
.
19
Shchelkunov, S. N..
2003
. Immunomodulatory proteins of orthopoxviruses.
Mol. Biol.
37
:
37
.
20
Upton, C., S. Slack, A. L. Hunter, A. Ehlers, R. L. Roper.
2003
. Poxvirus orthologous clusters: toward defining the minimum essential poxvirus genome.
J. Virol.
77
:
7590
.
21
McLysaght, A., P. F. Baldi, B. S. Gaut.
2003
. Extensive gene gain associated with adaptive evolution of poxviruses.
Proc. Natl. Acad. Sci. USA
100
:
15655
.
22
Gubser, C., S. Hue, P. Kellam, G. L. Smith.
2004
. Poxvirus genomes: a phylogenetic analysis.
J. Gen. Virol.
85
:
105
.
23
Fickenscher, H., S. Hor, H. Kupers, A. Knappe, S. Wittmann, H. Sticht.
2002
. The interleukin-10 family of cytokines.
Trends Immunol.
23
:
89
.
24
Moore, K. W., R. D. W. Malefyt, R. L. Coffman, A. O’Garra.
2001
. Interleukin-10 and the interleukin-10 receptor.
Annu. Rev. Immunol.
19
:
692
.
25
Dumoutier, L., J.-C. Renauld.
2002
. Viral and cellular interleukin-10 (IL-10)-related cytokines: from structures to functions.
Eur. Cytokine Network
13
:
5
.
26
Lalani, A. S., J. Barrett, G. McFadden.
2000
. Modulating chemokines: more lessons from viruses.
Immunol. Today
21
:
100
.
27
Murphy, P. M..
2001
. Viral exploitation and subversion of the immune system through chemokine mimicry.
Nature
2
:
116
.
28
Seet, B. T., G. McFadden.
2002
. Viral chemokine binding proteins.
J. Leukocyte Biol.
72
:
24
.
29
Holst, P. J., M. M. Rosenkilde.
2003
. Microbiological exploitation of the chemokine system.
Microbes Infect.
5
:
179
.
30
Barry, M., G. McFadden.
1997
. Virokines and viroceptors. D. G. Remick, and J. S. Friedland, eds.
Cytokines in Health and Disease
251
. Dekker, New York.
31
Barry, M., G. McFadden.
1997
. Virus encoded cytokines and cytokine receptors.
Parasitology
115
:
S89
.
32
Smith, S. A., G. J. Kotwal.
2001
. Virokines: novel immunomodulatory agents.
Exp. Opin. Biol. Ther.
1
:
343
.
33
McFadden, G., A. Lalani, H. Everett, P. Nash, X. Xu.
1998
. Virus encoded-receptors for cytokines and chemokines.
Semin. Cell Dev. Biol.
9
:
359
.
34
Carfi, A., C. A. Smith, P. J. Smolak, J. McGrew, D. C. Wiley.
1999
. Structure of a soluble secreted chemokine inhibitor vCCI (p35) from cowpox virus.
Proc. Natl. Acad. Sci. USA
96
:
12379
.
35
Alexander, J. M., C. A. Nelson, V. van Berkel, E. K. Lau, J. M. Studts, T. J. Brett, S. H. Speck, T. M. Handel, H. W. Virgin, D. H. Fremont.
2002
. Structural basis of chemokine sequestration by a herpesvirus decoy receptor.
Cell
111
:
343
.
36
Alcami, A..
2003
. Structural basis of the herpesvirus M3-chemokine interaction.
Trends Microbiol.
11
:
191
.
37
Lalani, A. S., K. Graham, K. Mossman, K. Rajarathnam, I. Clark-Lewis, D. Kelvin, G. McFadden.
1997
. The purified myxoma virus γ-interferon receptor homolog, M-T7, interacts with the heparin binding domains of chemokines.
J. Virol.
71
:
4356
.
38
Mossman, K., P. Nation, J. Macen, M. Garbutt, A. Lucas, G. McFadden.
1996
. Myxoma virus M-T7, a secreted homolog of the interferon-γ receptor, is a critical virulence factor for the development of myxomatosis in European rabbits.
Virology
215
:
17
.
39
Upton, C., K. Mossman, G. McFadden.
1992
. Encoding of a homolog of the IFN-γ receptor by myxoma virus.
Science
258
:
1369
.
40
Alcamí, A., J. A. Symons, P. D. Collins, T. J. Williams, G. L. Smith.
1998
. Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus.
J. Immunol.
160
:
624
.
41
Smith, C. A., T. D. Smith, P. J. Smolak, D. Friend, H. Hagen, M. Gerhart, L. Park, D. J. Pickup, D. Torrance, K. Mohler, et al
1997
. Poxvirus genomes encode a secreted soluble protein that preferentially inhibits β chemokine activity yet lacks sequence homology to known chemokine receptors.
Virology
236
:
316
.
42
Graham, K. A., A. S. Lalani, J. L. Macen, T. L. Ness, M. Barry, L.-Y. Liu, A. Lucas, I. Clark-Lewis, R. W. Moyer, G. McFadden.
1997
. The T1/35kDa family of poxvirus secreted proteins bind chemokines and modulate leukocyte influx into virus infected tissues.
Virology
229
:
12
.
43
Lalani, A. S., T. L. Ness, R. Singh, J. K. Harrison, B. T. Seet, D. J. Kelvin, G. McFadden, R. W. Moyer.
1998
. Functional comparisons among members of the poxvirus T1/35kDa family of soluble CC-chemokine inhibitor glycoproteins.
Virology
250
:
173
.
44
van Berkel, V., J. Barrett, H. L. Tiffany, D. H. Fremont, P. M. Murphy, G. McFadden, S. H. Speck, H. W. Virgin.
2000
. Identification of a gammaherpesvirus selective chemokine binding protein that inhibits chemokine action.
J. Virol.
74
:
6741
.
45
Parry, B. C., J. P. Simas, V. P. Smith, C. A. Stewart, A. C. Minson, S. Efstathiou, A. Alcamí.
2000
. A broad spectrum secreted chemokine binding protein encoded by a herpesvirus.
J. Exp. Med.
191
:
573
.
46
Alcami, A., S. Efstathiou.
2000
. Soluble chemokine binding proteins are also encoded by herpesviruses.
Immunol. Today
21
:
526
.
47
Webb, L. M. C., I. Clark-Lewis, A. Alcami.
2003
. The gammaherpesvirus chemokine binding protein binds to the N terminus of CXCL8.
J. Virol.
77
:
8588
.
48
Webb, L. M. C., V. P. Smith, A. Alcami.
2004
. The gammaherpesvirus chemokine binding protein can inhibit the interaction of chemokines with glycosaminoglycans.
FASEB J.
18
:
571
.
49
Bryant, N. A., N. Davis-Poynter, A. Vanderplasschen, A. Alcami.
2003
. Glycoprotein G isoforms from some alphaherpesviruses function as broad-spectrum chemokine binding proteins.
EMBO J.
22
:
833
.
50
Lindow, M., H. R. Luttichau, T. W. Schwartz.
2003
. Viral leads for chemokine-modulatory drugs.
Trends Pharmacol. Sci.
24
:
126
.
51
Proudfoot, A. E. I., C. A. Power, C. Rommel, T. N. C. Wells.
2003
. Strategies for chemokine antagonists as therapeutics.
Semin. Immunol.
15
:
57
.
52
Schwarz, M. K., T. N. Wells.
2002
. New therapeutics that modulate chemokine networks.
Nat. Rev. Drug Discov.
1
:
347
.
53
Liu, L. Y., A. Lalani, E. Dai, B. Seet, C. Macauley, R. Singh, L. Fan, G. McFadden, A. Lucas.
2000
. The viral anti-inflammatory chemokine-binding protein M-T7 reduces intimal hyperplasia after vascular injury.
J. Clin. Invest.
105
:
1613
.
54
Bedard, E. L. R., P. Kim, J. Jiang, N. Parry, L. Liu, H. Wang, B. Garcia, X. Li, G. McFadden, A. Lucas, R. Zhong.
2003
. Chemokine-binding viral protein M-T7 prevents chronic rejection in rat renal allografts.
Transplantation
76
:
249
.
55
Liu, L. Y., E. Dai, L. Miller, B. Seet, A. Lalani, C. Macauley, X. Li, H. W. Virgin, C. Bunce, P. Turner, et al
2004
. Viral chemokine-binding proteins inhibit inflammatory responses and aortic allograft transplant vasculopathy in rat models.
Transplantation
77
:
1652
.
56
Dabbagh, K., Y. Xiao, C. Smith, P. Stepick-Biek, S. G. Kim, W. J. Lamm, D. H. Liggitt, D. B. Lewis.
2000
. Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI.
J. Immunol.
165
:
3418
.
57
Bursill, C. A., S. Cai, K. M. Channon, D. R. Greaves.
2003
. Adenoviral-mediated delivery of a viral chemokine binding protein blocks CC-chemokine activity in vitro and in vivo.
Immunology
207
:
187
.
58
Jensen, K. K., S.-C. Chen, R. W. Hipkin, M. T. Wiekowski, M. A. Schwarz, C.-C. Chou, J. P. Simas, A. Alcami, S. A. Lira.
2003
. Disruption of CCL21-induced chemotaxis in vitro and in vivo by M3, a chemokine-binding protein encoded by murine gammaherpesvirus 68.
J. Virol.
77
:
624
.
59
Pyo, R., K. K. Jensen, M. T. Wiekowski, D. Manfra, A. Alcami, M. B. Taubman, S. A. Lira.
2004
. Inhibition of intimal hyperplasia in transgenic mice conditionally expressing the chemokine-binding protein M3.
Am. J. Pathol.
164
:
2289
.
60
Proudfoot, A. E. I., T. M. Handel, Z. Johnson, E. K. Lau, P. LiWang, I. Clark-Lewis, F. Borlat, T. N. C. Wells, M. H. Kosco-Vilbois.
2003
. Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines.
Proc. Natl. Acad. Sci. USA
100
:
1885
.
61
Lau, E. K., C. D. Paavola, Z. Johnson, J.-P. Gaudry, E. Geretti, F. Borlaat, A. J. Kungl, A. E. Proudfoot, T. M. Handel.
2004
. Identification of glycosaminoglycan binding site of the CC chemokine, MCP-1; implications for structure and function in vivo.
J. Biol. Chem.
279
:
22294
.
62
Johnson, Z., C. A. Power, C. Weiss, F. Rintelen, H. Ji, T. Rickle, M. Camps, T. N. C. Wells, M. K. Schwarz, A. E. I. Proudfoot, C. Rommel.
2004
. Chemokine inhibition—why, when, where, which and how?.
Biochem. Soc. Trans.
32
:
366
.
63
Luttichau, B. H., J. Stine, T. P. Boesen, A. H. Johnsen, D. Chanry, J. Gerstoft, T. W. Schwartz.
2000
. A highly selective CC chemokine receptor (CCR)8 antagonist encoded by the poxvirus Molluscum contagiosum.
J. Exp. Med.
191
:
171
.
64
Luttichau, H. R., J. Gerstoft, T. W. Schwartz.
2001
. MC148 encoded by human Molluscum contagiosum poxvirus is an antagonist for human but not murine CCR8.
J. Leukocyte Biol.
70
:
277
.
65
Laing, K. J., C. J. Secombes.
2004
. Chemokines.
Dev. Comp. Immunol.
28
:
443
.
66
deBruyne, L. A., K. Li, D. K. Bishop, J. S. Bromberg.
2000
. Gene transfer of virally encoded chemokine antagonists vMIP-11 and MC148 prolongs cardiac allograft survival and inhibits donor-specific immunity.
Gene Ther.
7
:
575
.
67
Weber, K. S. C., H. J. Grone, M. Rocken, C. Klier, S. H. Gu, R. Wank, A. E. I. Proudfoot, P. J. Nelson, C. Weber.
2001
. Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II.
Eur. J. Immunol.
31
:
2458
.
68
Damon, I., P. M. Murphy, B. Moss.
1998
. Broad spectrum chemokine antagonistic activity of a human poxvirus chemokine homolog.
Proc. Natl. Acad. Sci. USA
95
:
6403
.
69
Gerard, C., B. J. Rollins.
2001
. Chemokines and disease.
Nat. Immunol.
2
:
108
.
70
Tran, P. B., R. J. Miller.
2003
. Chemokine receptors: signposts to brain development and disease.
Nat. Rev. Neurosci.
4
:
444
.
71
Minami, M., M. Satoh.
2003
. Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury.
Life Sci.
74
:
321
.
72
Takami, S., M. Minami, I. Nagata, S. Namura, M. Satoh.
2001
. Chemokine receptor antagonist peptide, viral MIP-II, protects the brain against focal cerebral ischemia in mice.
J. Cereb. Blood Flow Metab.
21
:
1430
.
73
Ghirnikar, R. S., Y. L. Lee, L. F. Eng.
2000
. Chemokine antagonist infusion attenuates cellular infiltration following spinal cord contusion injury in rat.
J. Neurosci. Res.
59
:
63
.
74
Chen, S., K. B. Bacon, L. Li, G. E. Garcia, Y. Xia, D. Lo, D. A. Thompson, M. A. Siani, T. Yamamoto, J. K. Harrison, L. Feng.
1998
. In vivo inhibition of CC and CX3C chemokine-induced leukocyte infiltration and attention of glomerulonephritis in Wistar-Kyoto (WKY) rats by vMIP-II.
J. Exp. Med.
188
:
193
.
75
Lindow, M., A. Nansen, C. Bartholdy, A. Stryhn, N. J. V. Hansen, T. P. Boesen, T. N. C. Wells, T. W. Schwartz, A. R. Thomsen.
2003
. The virus-encoded chemokine vMIP-II inhibits virus-induced Tc1-driven inflammation.
J. Virol.
77
:
7393
.
76
Mocellin, S., M. C. Panelli, E. Wang, D. Nagorsen, F. M. Marincola.
2003
. The dual role of IL-10.
Trends Immunol.
24
:
36
.
77
Asadullah, K., W. Sterry, H. D. Volk.
2003
. Interleukin-10 therapy—review of a new approach.
Am. Soc. Pharmacol. Exp. Ther.
55
:
241
.
78
Mocellin, S., F. Marincola, C. R. Rossi, D. Nitti, M. Lise.
2004
. The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle.
Cytokine Growth Factor Rev.
15
:
61
.
79
Suzuki, T., H. Tahara, S. Narula, K. W. Moore, P. D. Robbins, M. T. Lotze.
1995
. Viral interleukin 10 (IL-10), the human herpes virus 4 cellular IL-10 homologue, induces local anergy to allogeneic and syngeneic tumors.
J. Exp. Med.
182
:
477
.
80
Lechman, E. R., D. Jaffurs, S. C. Ghivizzani, A. Gambotto, I. Kovesdi, Z. Mi, C. H. Evans, P. D. Robbins.
1999
. Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees.
J. Immunol.
163
:
2202
.
81
Apparailly, F., C. Verwaerde, C. Jacquet, C. Auriault, J. Sany, C. Jorgensen.
1998
. Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis.
J. Immunol.
160
:
5213
.
82
Apparailly, F., V. Millet, D. Noel, C. Jacquet, J. Sany, C. Jorgensen.
2002
. Tetracycline-inducible interleukin-10 gene transfer mediated by an adeno-associated virus: application to experimental arthritis.
Hum. Gene Ther.
13
:
1179
.
83
Whalen, J. D., E. L. Lechman, C. A. Carlos, K. Weiss, I. Kovesdi, J. C. Glorioso, P. D. Robbins, C. H. Evans.
1999
. Adenoviral transfer of viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws.
J. Immunol.
162
:
3625
.
84
Ma, Y., S. Thornton, L. E. Duwel, G. P. Boivin, E. H. Giannini, J. M. Leiden, J. A. Bluestone, R. Hirsch.
1998
. Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer.
J. Immunol.
161
:
1516
.
85
Carmody, E. E., E. M. Schwarz, J. E. Puzas, R. N. Rosier, R. J. O’Keefe.
2002
. Viral interleukin-10 gene inhibition of inflammation, osteoclastogenesis, and bone resorption in response to titanium particles.
Arthritis Rheum.
46
:
1298
.
86
Yang, S.-Y., B. Wu, L. Mayton, P. Mukherjee, P. D. Robbins, C. H. Evans, P. H. Wooley.
2004
. Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear debris-induced osteolysis.
Gene Ther.
11
:
483
.
87
Zhu, Z., D. Stevenson, J. E. Schechter, A. K. Mircheff, T. Ritter, L. Labree, M. D. Trousdale.
2004
. Prophylactic effect of IL-10 gene transfer on induced autoimmune dacryoadenitis.
Invest. Ophthalmol. Visual Sci.
45
:
1375
.
88
Jorgensen, C., F. Apparailly, F. Canovas, C. Verwaerde, C. Auriault, C. Jacquet, J. Sany.
1998
. Systemic viral interleukin-10 gene delivery prevents cartilage invasion by human rheumatoid synovial tissue engrafted in SCID mice.
Arthritis Rheum.
42
:
678
.
89
Kim, K.-N., S. Watanabe, Y. Ma, S. Thornton, E. H. Giannini, R. Hirsch.
2000
. Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer.
J. Immunol.
164
:
1576
.
90
Chen, D., Y. Ding, N. Zhang, B. Schroppel, S. Fu, W. Zang, H. Zhang, W. W. Hancock, J. S. Bromberg.
2003
. Viral IL-10 gene transfer inhibits the expression of multiple chemokine and chemokine receptor genes induced by inflammatory or adaptive immune stimuli.
Am. J. Transplant.
12
:
1538
.
91
Lechman, E. R., A. Keravala, J. Nash, S.-H. Kim, Z. Mi, P. D. Robbins.
2003
. The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the immunizing antigen.
Gene Ther.
10
:
2029
.
92
Salgar, S. K., D. Yang, P. Ruiz, J. Miller, A. G. Tzakis.
2004
. Viral interleukin-10 gene therapy to induce tolerance to solid organ transplants in mice.
Transplant. Proc.
36
:
397
.
93
Qin, L., Y. Ding, H. Tahara, J. S. Bromberg.
2001
. Viral IL-10-induced immunosuppression requires Th2 cytokines and impairs APC function within the allograft.
J. Immunol.
166
:
2385
.
94
DeBruyne, L. A., K. Li, S. Y. Chan, L. Qin, D. K. Bishop, J. S. Bromberg.
1998
. Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses.
Gene Ther.
5
:
1079
.
95
Qin, L., K. D. Chavin, Y. Ding, H. Tahara, J. P. Favaro, J. E. Woodward, T. Suzuki, P. D. Robbins, M. T. Lotze, J. S. Bromberg.
1996
. Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival.
J. Immunol.
156
:
2316
.
96
Fu, S., D. Chen, X. Mao, N. Zhang, Y. Ding, J. S. Bromberg.
2003
. Feline immunodeficiency virus-mediated viral interleukin-10 gene transfer prolongs non-vascularized cardiac allograft survival.
Am. J. Transplant.
3
:
552
.
97
Zuo, X.-J., C. Wang, D. Carpenter, Y. Okada, E. Nicolaidou, M. Toyoda, A. Trento, S. C. Jordan.
2001
. Prolongation of allograft survival with viral IL-10 transfection in a highly histoincompatible model of rat heart allograft rejection.
Transplantation
71
:
686
.
98
Yang, J., A. Reutzel-Selke, C. Steier, A. Jurisch, S. G. Tullius, B. Sawitzki, J. Kolls, H.-D. Volk, T. Ritter.
2003
. Targeting of macrophage activity by adenovirus-mediated intragraft overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 ameliorates adenovirus-mediated chronic graft injury, whereas stimulation of macrophages by overexpression of IFN-γ accelerates chronic graft injury in a rat renal allograft model.
J. Am. Soc. Nephrol.
14
:
214
.
99
Drazan, K. E., L. Wu, K. M. Olthoff, O. Jurim, R. W. Busuttil, A. Shaked.
1995
. Transduction of hepatic allografts achieves local levels of viral IL-10 which suppress alloreactivity in vitro.
J. Surg. Res.
59
:
219
.
100
Fujisawa, K., S. Saito, Y. Okada, T. Fujiwara, T. Yagi, H. Iwagaki, N. Tanaka.
2003
. Suppression of allogeneic response by viral IL-10 gene transfer.
Cell Transplant.
12
:
379
.
101
Nast, C. C., A. Moudgil, X. J. Zuo, M. Toyoda, S. C. Jordan.
1997
. Long-term allograft acceptance in a patient with posttransplant lymphoproliferative disorder: correlation with intragraft viral interleukin-10.
Transplantation
64
:
1578
.
102
Takayama, T., Y. Nishioka, L. Lu, M. T. Lotze, H. Tahara, A. W. Thomson.
1998
. Retroviral delivery of viral interleukin-10 into myeloid dendritic cells markedly inhibits their allostimulatory activity and promotes the induction of T-cell hyporesponsiveness.
Transplantation
66
:
1567
.
103
Adachi, O., E. Yamato, S. Kawamoto, M. Yamamoto, H. Tahara, K. Tabayashi, J.-I. Miyazaki.
2002
. High-level expression of viral interleukin-10 in cardiac allografts fails to prolong graft survival.
Transplantation
74
:
1603
.
104
Salgar, S. K., D. Yang, P. Ruiz, J. Miller, A. G. Tzakis.
2004
. Viral interleukin-10-engineered autologous hematopoietic stem cell therapy: a novel gene therapy approach to prevent graft rejection.
Hum. Gene Ther.
15
:
131
.
105
Verwaerde, C., M.-C. Naud, A. Delanoye, M. Wood, B. Thillaye-Goldenberg, C. Aurialt, Y. de Kozak.
2003
. Ocular transfer of retinal glial cells transduced ex vivo with adenovirus expressing viral IL-10 or CTLA4-Ig inhibits experimental autoimmune uveoretinitis.
Gene Ther.
10
:
1970
.
106
de Kozak, Y., B. Thillaye-Goldenberg, M.-C. Naud, A. V. Da Costa, C. Auriault, C. Verwaerde.
2002
. Inhibition of experimental autoimmune uveoretinitis by systemic and subconjunctival adenovirus-mediated transfer of the viral IL-10 gene.
Clin. Exp. Immunol.
130
:
212
.
107
Henke, P. K., L. A. DeBrunye, R. M. Strieter, J. S. Bromberg, M. Prince, A. M. Kadell, M. Sarkar, F. Londy, T. W. Wakefield.
2000
. Viral IL-10 gene transfer decreases inflammation and cell adhesion molecule expression in a rat model of venous thrombosis.
J. Immunol.
164
:
2131
.
108
Myers, D. D., Jr, A. E. Hawley, D. M. Farris, A. M. Chapman, S. K. Wrobleski, P. K. Henke, T. W. Wakefield.
2003
. Cellular IL-10 is more effective than viral IL-10 in decreasing venous thrombosis.
J. Surg. Res.
112
:
168
.
109
Kawamoto, S., Y. Nitta, F. Tashiro, A. Nakano, E. Yamato, H. Tahara, K. Tabayashi, J.-I. Miyazaki.
2001
. Suppression of Th1 cell activation and prevention of autoimmune diabetes in NOD mice by local expression of viral IL-10.
Int. Immunol.
13
:
685
.
110
Yang, Z., M. Chen, R. Wu, L. B. Fialkow, J. S. Bromberg, M. McDuffie, A. Naji, J. L. Nadler.
2002
. Suppression of autoimmune diabetes by viral IL-10 gene transfer.
J. Immunol.
168
:
6479
.
111
Higuchi, N., H. Maruyama, T. Kuroda, S. Kameda, N. Iino, H. Kawachi, Y. Nishikawa, H. Hanawa, H. Tahara, J. Miyazaki, F. Gejyo.
2003
. Hydrodynamics-based delivery of the viral interleukin-10 gene suppresses experimental crescentic glomerulonephritis in Wistar-Kyoto rats.
Gene Ther.
10
:
1297
.
112
Whalen, J. D., A. W. Thomson, L. Lu, P. D. Robbins, C. H. Evans.
2001
. Viral IL-10 gene transfer inhibits DTH responses to soluble antigens: evidence for involvement of genetically modified dendritic cells and macrophages.
Mol. Ther.
4
:
543
.
113
Ding, W., S. Beissert, L. Deng, E. Miranda, C. Cassetty, K. Seiffert, K. L. Campton, Z. Yan, G. F. Murphy, J. A. Bluestone, R. D. Granstein.
2003
. Altered cutaneous immune parameters in transgenic mice overexpressing viral IL-10 in the epidermis.
J. Clin. Invest.
111
:
1923
.
114
Minter, R. M., M. A. Ferry, M. E. Murday, C. L. Tannahill, F. R. Bahjat, C. Oberholzer, A. Oberholzer, D. LaFace, B. Hutchins, S. Wen, et al
2001
. Adenoviral delivery of human and viral IL-10 in murine sepsis.
J. Immunol.
167
:
1053
.
115
Verwaerde, C., K. Thiam, A. Delanoye, R. Fernandez-Gomez, J.-C. D’Halluin, C. Auriault.
1999
. Systemic delivery of an adenovirus expressing EBV-derived vIL-10 in mice infected with Schistosoma mansoni or Leishmania amazonensis: controversial effects on the development of pathological parameters.
Eur. Cytokine Network
10
:
161
.
116
Yang, S., B. Wu, L. Mayton, C. H. Evans, P. D. Robbins, P. H. Wooley.
2002
. IL-1Ra and vIL-10 gene transfer using retroviral vectors ameliorates particle-associated inflammation in the murine air pouch model.
Inflamm. Res.
51
:
342
.
117
Rosengard, A. M., J. M. Ahearn.
1999
. Viral complement regulatory proteins.
Immunopharmacology
42
:
99
.
118
Favoreel, H. W., G. R. Van de Walle, H. J. Nauwynck, M. B. Pensaert.
2003
. Virus complement evasion strategies.
J. Gen. Virol.
84
:
1
.
119
Bernet, J., J. Mullick, A. K. Singh, A. Sahu.
2003
. Viral mimicry of the complement system.
J. Biosci.
28
:
249
.
120
Blue, C. E., O. B. Spiller, D. J. Blackbourn.
2004
. The relevance of complement to virus biology.
Virology
319
:
176
.
121
Howard, J., D. E. Justus, A. V. Totmenin, S. Shchelkunov, G. J. Kotwal.
1998
. Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat.
J. Leukocyte Biol.
64
:
68
.
122
Kotwal, G. J..
2000
. Poxviral mimicry of complement and chemokine system components: what’s the end game?.
Immunol. Today
21
:
242
.
123
Mullick, J., A. Kadam, A. Sahu.
2003
. Herpes and pox viral complement control proteins: “the mask of self.”.
Trends Immunol.
24
:
500
.
124
Kotwal, G. J., B. Moss.
1988
. Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins.
Nature
335
:
176
.
125
Kotwal, G. J., S. N. Isaacs, R. McKenzie, M. M. Frank, B. Moss.
1990
. Inhibition of the complement cascade by the major secretory protein of vaccinia virus.
Science
250
:
827
.
126
Isaacs, S. N., G. J. Kotwal, B. Moss.
1992
. Vaccinia virus complement-control protein prevents antibody-dependent complement-enhanced neutralization of infectivity and contributes to virulence.
Proc. Natl. Acad. Sci. USA
89
:
628
.
127
Murthy, K. H., S. A. Smith, V. K. Ganesh, K. W. Judge, N. Mullin, P. N. Barlow, C. M. Ogata, G. J. Kotwal.
2001
. Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans.
Cell
104
:
301
.
128
Anderson, J. B., S. A. Smith, R. van Wijk, S. Chien, G. J. Kotwal.
2002
. Vaccinia virus complement control protein amerliorates hyperacute xenorejection by inhibiting xenoantibody binding.
Transplant. Proc.
34
:
3277
.
129
Jha, P., G. J. Kotwal.
2003
. Vaccinia complement control protein: multi-functional protein and a potential wonder drug.
J. Biosci.
28
:
265
.
130
Scott, M. J., P. T. Burch, P. Jha, J. C. Peyton, G. J. Kotwal, W. G. Cheadle.
2003
. Vaccinia virus complement control protein increases early bacterial clearance during experimental peritonitis.
Surg. Infect.
4
:
317
.
131
Anderson, J. B., S. A. Smith, G. J. Kotwal.
2002
. Vaccinia virus complement control protein inhibits hyperacute xenorejection.
Transplant. Proc.
34
:
1083
.
132
Anderson, J. B., S. A. Smith, R. van Wijk, S. Chien, G. J. Kotwal.
2003
. Vaccinia virus complement control protein inhibits hyperacute xenorejection in a guinea pig-to-rat heterotopic cervical cardiac xenograft model by blocking both xenoantibody and complement pathway activation.
Transplant Immunol.
11
:
129
.
133
Kahn, D., S. A. Smith, G. J. Kotwal.
2003
. Dose-dependent inhibition of complement in baboons by vaccinia virus complement control protein: implications in xenotransplantation.
Transplant. Proc.
35
:
1606
.
134
Jha, P., S. A. Smith, D. E. Justus, G. J. Kotwal.
2003
. Prolonged retention of vaccinia virus complement control protein following IP injection: implications in blocking xenorejection.
Transplant. Proc.
35
:
3160
.
135
Mastellos, D., D. Morikis, S. N. Isaacs, M. C. Holland, C. W. Strey, J. D. Lambris.
2003
. Complement structure, functions, evolution, and viral molecular mimicry.
Immunol. Res.
27
:
367
.
136
Cozzi, E., E. Ancona.
2003
. Xenotransplantation, where do we stand?.
J. Nephrol.
16
:
S16
.
137
Hoerbelt, R., J. C. Madsen.
2004
. Feasibility of xeno-transplantation.
Surg. Clin. North Am.
84
:
289
.
138
Al-Mohanna, F., R. Parhar, G. J. Kotwal.
2001
. Vaccinia virus complement control protein is capable of protecting xenoendothelial cells from antibody binding and killing by human complement and cytotoxic cells.
Transplantation
71
:
796
.
139
Kotwal, G. J., C. G. Miller, D. E. Justus.
1998
. The inflammation modulatory protein (IMP) of cowpox virus drastically diminishes the tissue damage by down-regulating cellular infiltration resulting from complement activation.
Mol. Cell. Biochem.
185
:
39
.
140
Kotwal, G. J., D. K. Lahiri, R. Hicks.
2002
. Potential intervention by vaccinia virus complement control protein of the signals contributing to the progression of central nervous system injury to Alzheimer’s Disease.
Ann. NY Acad. Sci.
973
:
317
.
141
Hicks, R. R., K. L. Keeling, M.-Y. Yang, S. A. Smith, A. M. Simons, G. J. Kotwal.
2002
. Vaccinia virus complement control protein enhances functional recovery after traumatic brain injury.
J. Neurotrauma
16
:
705
.
142
Reynolds, D. N., S. A. Smith, Y.-P. Zhang, D. K. Lahirl, D. J. Morassutti, C. B. Shields, G. J. Kotwal.
2003
. Vaccinia virus complement control protein modulates inflammation following spinal cord injury.
Ann. NY Acad. Sci.
1010
:
534
.
143
Silverman, G. A., P. I. Bird, R. W. Carrell, F. C. Church, P. B. Coughlin, P. G. W. Gettins, J. A. Irving, D. A. Lomas, C. J. Luke, R. W. Moyer, et al
2001
. The Serpins are an expanding superfamily of structurally similar but functionally diverse proteins.
J. Biol. Chem.
276
:
33293
.
144
Ye, S., E. J. Goldsmith.
2001
. Serpins and other covalent protease inhibitors.
Curr. Opin. Struct. Biol.
11
:
740
.
145
Gettins, P. G. W..
2002
. Serpin structure, mechanism and function.
Chem. Rev.
102
:
4751
.
146
van Gent, D., P. Sharp, K. Morgan, N. Kalsheker.
2003
. Serpins: structure, function and molecular evolution.
Int. J. Biochem. Cell Biol.
35
:
1536
.
147
Turner, P. C., P. W. Musy, R. W. Moyer.
1995
. Poxvirus serpins. G. McFadden, Jr, ed.
Viroceptors, Virokines and Related Immune Modulators Encoded by DNA Viruses
67
. R. G. Landes, Austin, TX.
148
Turner, P. C., R. Moyer.
2001
. Serpins enable poxviruses to evade immune defenses.
ASM News
67
:
201
.
149
Lomas, D. A., D. L. Evans, C. Upton, G. McFadden, R. W. Carrell.
1993
. Inhibition of plasmin, urokinase, tissue plasminogen activator, and C1S by a myxoma virus serine proteinase inhibitor.
J. Biol. Chem.
268
:
516
.
150
Nash, P., A. Lucas, G. McFadden.
1997
. SERP-1, a poxvirus-encoded serpin, is expressed as a secreted glycoprotein that inhibits the inflammatory response to myxoma virus infection. F. C. Church, Jr, and D. D. Cunningham, Jr, and D. Ginsburg, Jr, and M. Hoffman, Jr, and S. R. Stone, Jr, and D. M. Tollefsen, Jr, eds.
Chemistry and Biology of Serpins
195
. Oxford Univ. Press, New York.
151
Nash, P., A. Whitty, J. Handwerker, J. Macen, G. McFadden.
1998
. Inhibitory specificity of the anti-inflammatory myxoma virus serpin, SERP-1.
J. Biol. Chem.
273
:
20982
.
152
Upton, C., J. L. Macen, D. S. Wishart, G. McFadden.
1990
. Myxoma virus and malignant rabbit fibroma virus encode a serpin-like protein important for virus virulence.
Virology
179
:
618
.
153
Macen, J. L., C. Upton, N. Nation, G. McFadden.
1993
. SERP-1, a serine proteinase inhibitor encoded by myxoma virus, is a secreted glycoprotein that interferes with inflammation.
Virology
195
:
348
.
154
Lucas, A., G. McFadden.
1999
. Harvesting viral proteins.
Can. Med. Assoc. J.
16
:
1134
.
155
Lucas, A., L. Liu, J. Macen, P. Nash, E. Dai, M. Stewart, K. Graham, W. Etches, L. Boshkov, P. N. Nation, et al
1996
. Virus-encoded serine proteinase inhibitor SERP-1 inhibits atherosclerotic plaque development after balloon angioplasty.
Circulation
94
:
2890
.
156
Lucas, A., E. Dai, L. Liu, H. Guan, P. Nash, G. McFadden, I. Miller.
2000
. Transplant vasculopathy: viral anti-inflammatory serpin regulation of atherogenesis.
J. Heart Lung Transplant.
19
:
1029
.
157
Hatton, M. W. C., B. Ross, S. M. R. Southward, A. Lucas.
2000
. Metabolism and distribution of the virus-encoded serine proteinase inhibitor SERP-1 in healthy rabbits.
Metab. Clin. Exp.
49
:
1449
.
158
Bot, I., J. H. von der Thusen, M. M. P. C. Donners, A. Lucas, M. L. Fekkes, S. C. A. de Jager, J. Kuiper, M. J. A. P. Daemen, T. J. C. van Berkel, S. Heeneman, E. A. L. Biessen.
2003
. Serine protease inhibitor Serp-1 strongly impairs atherosclerotic lesion formation and induces a stable plaque phenotype in ApoE−/− mice.
Circ. Res.
93
:
464
.
159
Miller, L., E. Dai, P. Nash, L. Liu, C. Icton, D. Klironomous, L. Fan, P. N. Nation, R. Zhong, G. McFadden, A. Lucas.
2000
. Inhibition of transplant vasculopathy in a rat aortic model after infusion of an anti-inflammatory viral serpin.
Circulation
101
:
1598
.
160
Hausen, B., K. Boeke, G. J. Berry, R. E. Morris.
2001
. Viral serine proteinase inhibitor (Serp-1) effectively decreases the incidence of graft vasculopathy in heterotopic heart allografts.
Transplantation
72
:
364
.
161
Dai, E., H. Guan, L. Liu, S. Little, G. McFadden, S. Vaziri, H. Cao, I. A. Ivanova, L. Bocksch, A. Lucas.
2003
. Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury.
J. Biol. Chem.
278
:
18563
.
162
Maksymowych, W. P., N. Nation, P. D. Nash, J. Macen, A. Lucas, G. McFadden, A. S. Russell.
1996
. Amelioration of antigen-induced arthritis in rabbits treated with a secreted viral serine proteinase inhibitor.
J. Rheumatol.
23
:
878
.
163
Porter, S..
2000
. Human immune response to recombinant human proteins.
J. Pharm. Sci.
90
:
1
.
164
Koren, E., L. A. Zuckerman, A. R. Mire-Sluis.
2002
. Immune responses to therapeutic proteins in humans—clinical significance, assessment and prediction.
Curr. Pharm. Biotechnol.
3
:
349
.
165
Chamberlain, P., A. R. Mire-Sluis.
2003
. An overview of scientific and regulatory issues for the immunogenicity of biological products.
Dev. Biol. (Basel)
112
:
3
.
166
Adair, F., D. Ozanne.
2002
. The immunogenicity of therapeutic proteins.
BioPharm.
15
:
30
.
167
Schellekens, H..
2003
. Immunogenicity of therapeutic proteins.
Nephrol. Dial. Transplant.
18
:
1257
.
168
Schellekens, H..
2002
. Bioequivalence and the immunogenicity of biopharmaceuticals.
Nat. Rev. Drug Discov.
1
:
457
.
169
Schellekens, H..
2002
. Immunogenicity of therapeutic proteins: clinical implications and future prospects.
Clin. Ther.
24
:
1720
.
170
Schellekens, H..
2003
. The immunogenicity of biopharmaceuticals.
Neurology
61
:(Suppl. 5):
811
.
171
Indiveri, F., G. Murdaca.
2002
. Immunogenicity of erythropoietin and other growth factors.
Rev. Clin. Exp. Hematol. Suppl.
1
:
7
.
172
Kelley, G..
2002
. EPO saga to augur regulatory change?.
BioPharm. Int.
15
:
44
.
173
Casadevall, N., J. Nataf, B. Viron, A. Kolta, J.-J. Kiladjian, P. Martin-Dupont, P. Michaud, T. Papo, V. Ugo, I. Teyssander, et al
2002
. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin.
N. Engl. J. Med.
346
:
469
.
174
Chirino, A. J., M. L. Ary, S. A. Marshall.
2004
. Minimizing the immunogenicity of protein therapeutics.
Drug Discov. Today
9
:
82
.
175
Wadhwa, M., C. Bird, P. Dilger, R. Gaines-Das, R. Thorpe.
2003
. Strategies for detection, measurement and characterization of unwanted antibodies induced by therapeutic biologicals.
J. Immunol. Methods
278
:
1
.
176
Gonzales, N. R., P. Schuck, J. Schlom, S. V. S. Kashmiri.
2002
. Surface plasmon resonance-based competition assay to assess the sera reactivity of variants of humanized antibodies.
J. Immunol. Methods
268
:
197
.
177
Fruh, K., K. Simmen, B. G. M. Luukkonen, Y. C. Bell, P. Ghazal.
2001
. Virogenomics: a novel approach to antiviral drug discovery.
Res. Focus Rev.
6
:
621
.
178
DeFilippis, V., C. Raggo, A. Moses, K. Fruh.
2003
. Functional genomics in virology and antiviral drug discovery.
Trends Biotechnol.
21
:
452
.
179
Kellam, P..
2001
. Post-genomic virology: the impact of bioinformatics, microarrays and proteomics on investigating host and pathogen interactions.
Rev. Med. Virol.
11
:
313
.
180
Anderson, N. G., J. L. Gerin, N. L. Anderson.
2003
. Global screening for human viral pathogens.
Emerg. Infect. Dis.
9
:
768
.
181
Mossman, K., C. Upton, G. McFadden.
1995
. The myxoma virus-soluble interferon-γ receptor homolog, M-T7, inhibits interferon-γ in a species-specific manner.
J. Biol. Chem.
270
:
3031
.