Tumor necrosis factor-alpha in experimental autoimmune neuritis****☆

Xijing Mao1, 2, Hongliang Zhang1, 2, Jie Zhu1, 2

1Department of Neurology, First Hospital of Jilin University, Changchun  130021, Jilin Province, China
2Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden

Xijing Mao☆, M.D., Department of Neurology, First Hospital of Jilin University, Changchun  130021, Jilin Province, China; Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden

Corresponding author: Jie Zhu, M.D., Associated professor, Department of Neurology, First Hospital of Jilin University, Changchun  130021, Jilin Province, China; Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
Jie.Zhu@ki.se

Abstract
Tumor necrosis factor-α (TNF-α) plays a key role in the pathogenesis of experimental autoimmune neuritis (EAN) as well as Guillain-Barr? syndrome. The proposed pathogenesis of TNF-α associated neuropathies involves immune-mediated attack to blood-nerve barrier, aggravated production of pro-inflammatory cytokines, and the induction of Schwann cells apoptosis. TNF-α may play a regulatory role by increasing production of interleukin-1 in macrophages, attenuating T cell receptor signaling and regulating apoptosis of potentially autoreactive T cells in EAN. The data suggest that antagonizing TNF-α functions or suppressing TNF-α production may be useful in the acute phase of EAN treatment, but further studies are required.
Key Words: tumor necrosis factor-α; experimental autoimmune neuritis; Guillain-Barr? syndrome; autoimmune; neurobiology; immune disease; review

INTRODUCTION
  
Experimental autoimmune neuritis (EAN) is an acute inflammatory demyelinating neuropathy that is used as an animal model for investigating human Guillain-Barr? syndrome (GBS). Numerous inflammatory cytokines play pivotal roles in initiating, enhancing and perpetuating pathophysiological procedure in EAN[1]. Tumor necrosis factor-α (TNF-α), a pleiotropic pro-inflammatory cytokine, has been identified as a key player in the pathogenesis of immune-mediated inflammatory demyelinating disorders of the peripheral nervous system, but the exact role of TNF-α in EAN pathogenesis remains unclear. This article reviewed updated evidence that TNF-α contributes to the pathogenesis of EAN and is considered as a therapeutic target for EAN.

IMMUNE PATHOGENESIS IN EAN

GBS is defined as an organ-specific immune-mediated disorder resulting from a synergistic interaction between cellular and humoral immune responses to incompletely characterized antigens in the peripheral nervous system[2]. However, the exact mechanism of GBS remains poorly understood. EAN shares clinical, histopathological, and electrophysiological features with GBS and is therefore used as an animal model to explore the pathogenesis of GBS[3]. EAN can be actively induced by immunization with purified myelin proteins, such as P0 or P2 proteins or their peptides or adoptive transfer of antigen-specific autoreactive T cells[4]. EAN is pathologically characterized by breakdown of the blood-nerve barrier (BNB), robust accumulation of reactive T cells and macrophages in the peripheral nervous system (PNS) and demyelination of peripheral nerves[5]. To cross the BNB and provoke a local inflammatory response, circulating autoreactive T cells need to be activated in the periphery and produce pro-inflammatory cytokines including TNF-α, interleukin (IL)-1 and IL-6[6]. Macrophages, as professional antigen presenting cells, express major histocompatibility complex (MHC)-II and co-stimulatory B7 molecules, and are critical in T cell activation and autoimmune process triggering. In addition, macrophages are crucial in the effector phase of EAN damaging the myelin sheath by phagocytic attack and secretion of inflammatory mediators such as toxic oxygen radicals, arachidonic acid metabolites, complements and matrix metalloproteinases (MMPs)[7-8]. Schwann cells (SCs), myelinating and supporting axons of the PNS, are involved in T cell-mediated immune responses in GBS/EAN, as they are capable of degrading and phagocytosing exogenous antigens to act as non-professional antigen-presenting cells[9-10]. After stimulation with inflammatory cytokines, SCs express MHC-I and MHC-II
molecules, and are able to stimulate antigen specific T cell proliferation and secrete cytokines such as TNF-α, IL-1, IL-6, complements and nitrite oxide (NO)[9], which contribute to immunoregulation within the PNS. Humoral immunity also plays a role in the pathogenesis of EAN. Antibodies against nerve antigens participate in complement activation, antibody-dependent macrophage cytotoxicity, and reversible conduction failure[11]. Both cellular and humoral immunity may function synergistically in activating neuritogenic T cells and B cells, breaking down the BNB, thereby providing circulating anti-myelin antibodies and other inflammatory molecules access to the target tissues.

GENERAL BIOLOGICAL PROPERTIES OF TNF-α AND ITS RECEPTORS

The gene of murine TNF-α is located on chromosome 17, 70 kb proximal to the D region of the MHC-II, at a distance of 1 Mb to the MHC-II regions I (MHC II; IA and IE) and H2K[12]. The gene of human TNF-α is located on chromosome 6 containing the genes of the MHC-II[13-14]. This close genetic linkage to the MHC supports the possible involvement of TNF-α in autoimmune diseases[15]. TNF-α is synthesized as a monomeric type-2 transmembrane protein (tmTNF) that is inserted into the membrane as a homotrimer and cleaved by TNF-α converting enzyme (TACE; also named as ADAM17) to a 17 kD soluble circulating trimer (solTNF); the solTNF tends to dissociate at concentrations below nanomolar range, thereby losing its bioactivity[16-17]. All solTNF is derived from tmTNF, but not all tmTNF is cleaved to generate solTNF[18]. tmTNF contains a casein kinase I motif and can act as a receptor[19]. Under pathological conditions, tmTNF might additionally transmit apoptotic signals[20-21] and stimulate T cells to reversely induce the production of high amounts of IL-2 and adhesion molecules[17]. Both tmTNF and solTNF exert pleiotropic biological activities and can be produced by activated macrophages, lymphoid cells, mast cells, astrocytes, neurons and SCs[22-23]. The biological effects of both forms of TNF-α are mediated via its transmembrane receptors, TNF receptor type Ι (TNFR1, CD120a, p55/60) and TNF receptor type II (TNFR2, CD120b, p75/80), each of which utilizes a distinct signal pathway and exerts unique intracellular effects. TNFR1 and TNFR2 are co-expressed on all nucleated cell types[24], especially on the surfaces of activated CD4 and CD8 positive T cells[25] and of activated SCs in vivo or in vitro[26-28]. The TNFR1 binds preferably to solTNF by internalization, whereas TNFR2 binds preferably to tmTNF by shedding of the ligand-receptor complex[29]. The signaling pathways intracellularly induced by the two receptors differ to a great extent[30]. The binding of TNF-α to TNFR1 triggers a series of intracellular events that ultimately result in the activation of two major transcription factors, nuclear factor-κB (NF-κB) and c-Jun. Both are responsible for the expression of genes important for diverse biological processes, including cell growth and death, oncogenesis, immune and inflammatory responses[31]. Especially, NF-κB can induce a variety of anti-apoptotic factor productions, which is of importance for the regulation of the apoptotic machinery of the cell by TNFR1-mediated triggering[32]. In addition, there is an extensive cross talk between NF-κB and c-Jun. TNF-α-induced c-Jun NH2-terminal kinase (JNK) activation is strong and prolonged in cells in the absence of NF-κB, and the products of several NF-κB-activated genes inhibit the activation of JNK by TNF-α[33]. The binding of TNF-α to TNFR2 does not directly engage the apoptotic program, but relies on the induction of endogenous tmTNF, which subsequently activates TNFR1 to initiate cell death[34]. TNFR2 engagement leads to the binding of TNFR-associated factors 1 and 2 (TRAF1, 2), leading to NF-κB activation and cell survival[17]. However, multiple experimental approaches have shown that a majority of biological activities of TNF-α are initiated by TNFR1[31].
 In conclusion, the complexity of TNF-α-mediated pathophysiology is associated with the differential bioactivities of its transmembrane and soluble forms[35], as well as the differential functions of TNFR1 and TNFR2[36]. In addition, the differential timing, location and quantity of TNF-α, and the differential genetic background of the organism might also modulate to a great extent the biological function of TNF-α[37] .

ROLE OF TNF-α IN EAN: PATHOGENIC MEDIATOR OR BENEFICIAL FACTOR?

The possible pathogenic mechanisms of TNF-α in EAN are shown in Figure 1. TNF-α has been identified as a key player in the pathogenesis of EAN as well as GBS. Clinically, an increased level of TNF-α has been detected in serum and local sites of inflammation in GBS patients[38-40]. Even a positive correlation between elevated serum TNF-α levels and disease severity in GBS could be established with maximal expression levels at the peak of the disease[41]. Serum TNF-α levels decreased after immune therapy and were in parallel with the clinical recovery of patients with GBS[40]. Experimental data have demonstrated that TNF-α mRNA expression in the PNS was up-regulated at the height of clinical EAN[1]. Injection of TNF-α into the rat sciatic nerves resulted in inflammatory vascular changes within the endoneurium, together with demyelination and axonal degeneration[42]. An immunocytochemical study in EAN suggested that TNF-α positive macrophages appeared at around the time of onset of clinical signs[43]. As animals recovered, TNF-α immunoreactivity was no longer detectable. In addition, TNF-α contributing to neuropathic pain in EAN has been shown in recent studies involving cytokine neutralization, knockout mice, direct application of the cytokine and glucocorticoid therapy[44-45]. Anti-inflammatory compounds, such as rolipram, linomide and leflunomide, can strikingly suppress the clinical symptoms of EAN by inhibiting cell infiltration and down-regulating TNF-α production[46-48]. 
 

The breakdown of the BNB is a key feature at the onset of both GBS and EAN, which may be crucial in allowing activated T cell access peripheral nerves. TNF-α, an autocrine immunomodulator, can up-regulate the expression of MHC-II and adhesion molecules on macrophages to activate T cells[42, 49]. Activated T cells initiate a local immune reaction which results in increased vascular permeability and the breakdown of the BNB[50-51]. Moreover, TNF-α-induced MMPs promote macrophages recruitment into injured peripheral nerves[52]. TNF-α has also been implicated in the induction of SC apoptosis, which is mediated by the classical interaction of TNF-α and its TNFR1[53]. SC apoptosis may be a critical factor challenging nerve remyelination and regeneration during the course of EAN. SCs and T cells display different susceptibility to apoptosis induced by TNF-α. Rather low concentrations of local TNF-α can induce SC apoptosis in EAN, while much high levels induce T cell apoptosis[54]. Through activation of caspase-3, TNF-α seems to be implicated in SC apoptosis in the natural disease course of EAN[55]. In addition, TNF-α mediate demyelination and/or neuronal degeneration either directly or indirectly via the production of other pro-inflammatory cytokines, reactive oxygen species and NO[56-57]. TNF-α may cause damage to the adjacent myelin sheaths by increasing the level of  toxic oxygen radicals which also contribute to the pathogenesis of EAN[58-59]. Genetically, TNF-α promoter polymorphism is responsible for susceptibility to GBS[60]. TNF-α allele 2 can increase the transcription of TNF-α and is associated with high levels of TNF-α in GBS serum[61-63]. TNFR superfamily member 1A (TNFRSF1A) has interaction with TNF-α[64-65]. A genome-wide association study has identified the R92Q variant of the TNFRSF1A gene as a new susceptibility locus for multiple sclerosis (MS)[66-67]. In human, TNFRSF1A gene encoded protein is one of the major receptors for TNF-α[68-69]. This receptor can activate NF-κB, mediate apoptosis, and regulate inflammation[70-71]. Anti-apoptotic protein Bcl-2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TNFR-associated death domain (TRADD) and TRAF2 also have interaction with this receptor, and play regulatory roles in the signal transduction mediated by the receptor[72-74].
However, TNF-α might have a beneficial role in EAN. TNF-α has been reported to attenuate TCR signaling[75]. This modulatory activity of TNF-α on TCR signaling, directs TNF-α induced inflammation in the periphery to down-regulate auto-aggressiveness, or even prevents development of auto-reactive T cells in specific localities[76]. TNF-α plays an important role in the termination of lymphocyte responses, as indicated by the capacity of this molecule to promote activation-induced cell death in CD8+ T cells[77-79]. TNF-α can advance macrophages to produce IL-1 that can induce synthesis of nerve growth factor in transected nerves[80-81]. Similarly, TNF-α antagonists exacerbate MS, an autoimmune demyelinating disease in the central nervous system[82]. TNFR2 might have a protective role as demonstrated that TNFR2 increased after intravenous immunoglobulin G (IVIg) treatment in patients with acute motor axonal neuropathy, a subtype of GBS[83]. The inhibition of TNF-α lead to a decrease of T cell apoptosis during high dose human P2 protein therapy in AT-EAN rats, making TNF-α the principal candidate for mediating some of the effects of antigen therapy[84].
The harmful and beneficial effects of TNF-α may segregate at the level of TNFR1 and TNFR2. In TNFR1 deficient mice, antimyelin reactivity regresses with time, and tolerance to the immunizing antigen is established, indicating that immunosuppressive functions of TNF-α may be sufficiently exerted via TNFR2[22]. The maximal level of local TNFR1 in sciatic nerves occurred during the first week after chronic constriction peripheral nerve injury, while TNFR2 protein remained elevated till nerve regeneration[85]. This suggests that TNF-α and TNFR2 are not only involved in deleterious effects after nerve injury but might also be essential for successful nerve regeneration. The shift of TNF-α-TNFR1-TNFR2 balance toward TNFR2 at later time points after nerve injury also shows that TNFR2 acted as an endogenous TNF-α antagonist. In contrast, experimental autoimmune encephalomyelitis was exacerbated in TNFR1 and TNFR2 double deficient mice, similarly to that in TNF-α knockout mice[86]. In mice lacking the TNFR1, the clinical course of EAN is suppressed at the acute phase. Therefore, TNFR1 is clearly indicated as an important target for therapy.

TNF-α IS CONSIDERED AS A THERAPEUTIC TARGET IN EAN

A range of methods can be hypothesized to regulate TNF-α biology (Figure 2) by suppressing TNF-α production or antagonizing TNF-α activities. Suppressing TNF-α production focuses on the suppression of activation signals, on the modulation of gene transcription or translation, or on the processing and release of mature TNF-α. Antagonizing TNF-α activities include the generation and administration of soluble TNF-α receptors (sTNFRs), anti-TNF-α antibodies and TNF-α variants.
 

Suppressing TNF-α production in EAN
TACE is a member of the adamalysin family of MMPs and appears to be responsible for cleaving tmTNF to solTNF[87-89]. TACE is expressed in nerves of EAN animals and GBS patients, whereas no expression in controls, and T cells could be defined as the cellular source of TACE with peak expression levels at maximal clinical disease severity[90]. Blockade of the TACE results in the elimination of solTNF. Current TACE inhibitors include small-molecule dual TACE and MMP inhibitors, and specific TACE inhibitors[91]. BB-1101, an inhibitor of both MMP activity and TNF-α processing, is effective in preventing the development and significantly ameliorates disease severity in EAN[92]. A broad-spectrum inhibitors of TACE and other MMPs also attenuate the course of disease in EAN, although this is partly associated with inhibition of inflammation[92]. Selective TACE inhibitors, such as BMS-561392, without activity against MMPs, can achieve full efficacy in models of inflammation[91, 93].
In addition, rolipram, a phosphodiesterase type 4 inhibitor, is known as a TNF-α synthesis inhibitor, and has been shown to effectively inhibit manifestations of EAN[48]. Rolipram can markedly down-regulate antigen-driven T cell proliferation and cytokine gene expression of unfractionated human peripheral blood mononuclear cells[94] and suppress TNF-α production in vitro and in vivo[48, 95-96]. Rolipram elevates the regeneration of nerve fibers by inducing SCs and fibroblasts to secrete brain-derived neurotrophic factor in peripheral nerves[96]. Rolipram has also been shown to dose-dependently down-regulate the production of interferon-γ (IFN-γ), macrophage inflammatory protein-1a (MIP-la), MIP-2 and monocyte chemotactic protein-1 (MCP-1) as well as up-regulate IL-4 production in sciatic nerve sections from rolipram-treated EAN rats at maximum of clinical EAN[97]. Another phosphodiesterase inhibitor pentoxifylline has been demonstrated to exert multiple immunomodulatory effects in vitro and in vivo by a quite similar mechanisms as rolipram[98-99]. Moreover, rolipram is able to induce the secretion of adrenocorticotropic hormone and consequently to increase serum corticosterone concentrations[100-101]. Large doses of corticosterone can suppress EAN and raise rapid recovery from EAN[102]. Dehydroepiandrosterone (DHEA) is an abundant adrenal steroid in sera of human and has been reported to have anti-inflammatory, anti-proliferative and certain immune-regulating properties. DHEA can ameliorate the severity of EAN by suppressing the expression of TNF-α in the splenocytes of Lewis rats[103].
Small molecules such as minocycline, thalidomide and IL-10, as less specific inhibitors of TNF-α, have been used in the treatment of inflammatory conditions. Minocycline decreases TNF-α synthesis by inhibiting the transcription of TNF-α gene, inhibits MMPs, reduces cyclooxygenase-2 activity and prostaglandin E2 production, and attenuates apoptosis[104-107]. Thalidomide, as an immunomodulatory drug, can exert its inhibitory action through enhancing degradation of TNF-α mRNA[108-109]. IL-10 can inhibit TNF-α production by targeting TNF-α mRNA to inhibit its translation, and the efficacy of IL-10 in suppressing TNF-α expression is severely compromised in the absence of the 3′ AU-rich elements of TNF mRNA[110-111].
sTNFR acts as an antagonist of TNF-α in EAN
The sTNFRs are usually generated by cleaving the extracellular domain by MMPs from the transmembrane TNFRs of a complete receptor. The sTNFRs act as an inhibitor to TNF-α activity at high concentrations[112]. However, at low concentrations, sTNFRs can enhance TNF-α activity by stabilizing TNF-α molecules and by prolonging their availability for binding to cell surface receptors[113]. sTNFR1 is enhanced in GBS patients treated with IVIg, while TNF-α shows a decrease correlation the neurological recovery following plasma exchange and IVIg therapy[83, 114-115]. This may be due to the down-regulation of TNF-α production and sustained buffering of TNF-α by sTNFR1. IVIg might selectively induce transcription and secretion of anti-inflammatory cytokines, as evidenced in cultured human lymphocytes[116]. The sTNFR1 treatment effectively ameliorates the clinical and pathological signs of EAN: it can delay the onset, decrease the severity, shorten the duration of EAN, and reduce inflammatory cell infiltration into the PNS during EAN[117-118]. These suppressions are associated with reduction of P0 peptide specific T cell proliferation, Th1 cytokine IFN-γ secretion and TNF-α production[118]. In addition, sTNFR1 inhibits the development of EAN by modulating inflammation and BNB permeability[117]. Etanercept is a fully human dimeric fusion protein composed of a TNFR2 linked to the Fc portion of IgG-1 and can inhibit binding of TNF-a to TNFRs, rendering TNF-α biologically inactive[119]. Etanercept has been approved for the treatment of rheumatoid arthritis and psoriasis in clinic[120-122] .
Treatment with anti-TNF-α antibodies and dominant-negative inhibitor of solTNF in EAN
TNF-α binding autoantibodies increased significantly in sera and cerebrospinal fluid in the recovery phase of EAN[3]. These autoantibodies may prevent the binding of TNF-α to its specific cell surface receptor and act as a carrier protein to prevent rapid elimination of the cytokine from the circulation or modulate cytokine-induced intracellular signaling. In EAN, administration of anti-TNF-α antibody to rats greatly reduces disease severity and attenuates pathological changes[123]. Infliximab and adalimumab, as anti-TNF-α monoclonal antibodies, could neutralize the biology activity of TNF-α by binding to solTNF and tmTNF[119, 124-128]. Moreover, inhibition of TNF-α by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis in EAN[84]. Clinically, high doses of IVIg exert immune regulatory effects and have been proven useful in 60% of GBS patients and in certain autoimmune conditions[129-130]. Additionally, TNF-α variants, such as XENP345 and XPro1595, are described as dominant-negative inhibitor of TNFs (DN-TNFs)[131]. DN-TNFs neither bind to nor signal through the TNFR1 or TNFR2, but rapidly exchange subunits with solTNF homotrimers to form inactive mixed heterotrimers, effectively eliminating solTNF[131-132]. Due to this novel mechanism of action, DN-TNFs can selectively inhibit solTNF and do not inhibit tmTNF signaling[131, 133]. DN-TNFs can attenuate experimental arthritis without suppressing innate immunity to infection in mice[133]. The ability of DN-TNFs to be tmTNF-sparing and solTNF-selective may be ideal in clinical conditions where solTNF signaling mediates pathology, to ensure that the immune function of tmTNF is not compromised.

CONCLUSION

The pathogenic role of TNF-α in EAN include activation of T cells and macrophages, induction of SC apoptosis as well as the impairment of permeability of the BNB. However, the exact role of TNF-α in the pathogenesis of EAN remains unclear, and a potential neuroprotective role cannot be excluded. Therefore further studies are required to rationalize the application of TNF-α and anti-TNF-α in the treatment of GBS and EAN.

Contributors: Xijing Mao contributed to the designing and writing of the manuscript. Hongliang Zhang was responsible for revising the manuscript. Jie Zhu is responsible for supervising and revising the manuscript.
Competing interest: None declared.
Funding: The study is supported by grants from SADF (Insamlingsstiftelsen f?r Alzheimer-och Demensforskning) foundation, Swedish Medicine Association, Gamla Tj?narinnor foundation, Gun och Bertil Stohnes foundation and Swedish National Board of Health and Welfare
Ethical approval: No related content of ethics collision.

REFERENCES

[1] Zhu J, Bai XF, Mix E, et al. Cytokine dichotomy in peripheral nervous system influences the outcome of experimental allergic neuritis: dynamics of mRNA expression for IL-1 beta, IL-6, IL-10, IL-12, TNF-alpha, TNF-beta, and cytolysin. Clin Immunol Immunopathol. 1997;84(1):85-94.
[2] Kieseier BC, Kiefer R, Gold R, et al. Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system. Muscle Nerve. 2004;30(2):131-156.
[3] Zhu W, Mix E, Nennesmo I, et al. Anti-cytokine autoantibodies in experimental autoimmune neuritis in Lewis rats. Exp Neurol. 2004; 190(2):486-494.
[4] Maurer M, Gold R. Animal models of immune-mediated neuropathies. Curr Opin Neurol. 2002;15(5):617-622.
[5] Zhang Z, Zhang ZY, Fauser U, et al. Valproic acid attenuates inflammation in experimental autoimmune neuritis. Cell Mol Life Sci. 2008;65(24):4055-4065.
[6] Kieseier BC, Hartung HP, Wiendl H. Immune circuitry in the peripheral nervous system. Curr Opin Neurol. 2006;19(5): 437-445.
[7] Kiefer R, Kieseier BC, Stoll G, et al. The role of macrophages in immune-mediated damage to the peripheral nervous system. Prog Neurobiol. 2001;64(2):109-127.
[8] Maurer M, Toyka KV, Gold R. Cellular immunity in inflammatory autoimmune neuropathies. Rev Neurol (Paris). 2002;158(12 Pt 2):S7-15.
[9] Gold R, Toyka KV, Hartung HP. Synergistic effect of IFN-gamma and TNF-alpha on expression of immune molecules and antigen presentation by Schwann cells. Cell Immunol. 1995;165(1):65-70.
[10] Lilje O. The processing and presentation of endogenous and exogenous antigen by Schwann cells in vitro. Cell Mol Life Sci. 2002;59(12):2191-2198.
[11] Creange A, Sharshar T, Raphael JC, et al. Cellular aspect of neuroinflammation in Guillain-Barre syndrome: a key to a new therapeutic option? Rev Neurol (Paris). 2002;158(1):15-27.
[12] Muller U, Jongeneel CV, Nedospasov SA, et al. Tumour necrosis factor and lymphotoxin genes map close to H-2D in the mouse major histocompatibility complex. Nature. 1987;325(6101): 265-267.
[13] Nedwin GE, Naylor SL, Sakaguchi AY, et al. Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985;13(17): 6361-6373.
[14] Pachman LM, Fedczyna TO, Lechman TS, et al. Juvenile dermatomyositis: the association of the TNF alpha-308A allele and disease chronicity. Curr Rheumatol Rep. 2001;3(5):379-386.
[15] Benjamin R, Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today. 1990;11(4):137-142.
[16] Newton RC, Solomon KA, Covington MB, et al. Biology of TACE inhibition. Ann Rheum Dis. 2001;60 Suppl 3:iii25-32.
[17] Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244-279.
[18] Kast RE, Altschuler EL. Proposal for using small molecule tumor necrosis factor-alpha lowering agents, possibly bupropion, in aplastic anemia. Med Hypotheses. 2005;65(2):374-376.
[19] Eissner G, Kolch W, Scheurich P. Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev. 2004;15(5):353-366.
[20] Lugering A, Schmidt M, Lugering N, et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology. 2001;121(5):1145-1157.
[21] van Deventer SJ. Anti-tumour necrosis factor therapy in Crohn's disease: where are we now? Gut. 2002;51(3):362-363.
[22] Kollias G, Kontoyiannis D. Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments. Cytokine Growth Factor Rev. 2002;13(4-5):315-321.
[23] Qin Y, Cheng C, Wang H, et al. TNF-alpha as an autocrine mediator and its role in the activation of Schwann cells. Neurochem Res. 2008;33(6):1077-1084.
[24] MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal. 2002;14(6):477-492.
[25] Ware CF, Crowe PD, Vanarsdale TL, et al. Tumor necrosis factor (TNF) receptor expression in T lymphocytes. Differential regulation of the type I TNF receptor during activation of resting and effector T cells. J Immunol. 1991;147(12):4229-4238.
[26] Bonetti B, Valdo P, Stegagno C, et al. Tumor necrosis factor alpha and human Schwann cells: signalling and phenotype modulation without cell death. J Neuropathol Exp Neurol. 2001;59(1):74-84.
[27] Conti G RA, Scarpini E, et al. Inducible nitric oxide synthase (iNOS) in immune-mediated demyelination and Wallerian degeneration of the rat peripheral nervous system. Exp Neurol. 2004;187(2):350-358.
[28] Qin Y, Cheng C, Wang H, et al. TNF-alpha as an autocrine mediator and its role in the activation of Schwann cells. Neurochem Res. 2008;33(6):1077-1084.
[29] Vandenabeele P, Declercq W, Vanhaesebroeck B, et al. Both TNF receptors are required for TNF-mediated induction of apoptosis in PC60 cells. J Immunol. 1995;154(6):2904-2913.
[30] Ledgerwood EC, Pober JS, Bradley JR. Recent advances in the molecular basis of TNF signal transduction. Lab Invest. 1999; 79(9):1041-1050.
[31] Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296(5573):1634-1635.
[32] Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10(1):45-65.
[33] Papa S, Zazzeroni F, Pham CG, et al. Linking JNK signaling to NF-kappaB: a key to survival. J Cell Sci. 2004;117(Pt 22): 5197-5208.
[34] Grell M, Zimmermann G, Gottfried E, et al. Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF. Embo J. 1999;18(11):3034-3043.
[35] Grell M, Douni E, Wajant H, et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995;83(5):793-802.
[36] Mukai Y, Shibata H, Nakamura T, et al. Structure-function relationship of tumor necrosis factor (TNF) and its receptor interaction based on 3D structural analysis of a fully active TNFR1-selective TNF mutant. J Mol Biol. 2009;385(4): 1221-1229.
[37] Kollias G, Douni E, Kassiotis G, et al. On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Immunol Rev. 1999;169:175-194.
[38] Creange A, Belec L, Clair B, et al. Circulating tumor necrosis factor (TNF)-alpha and soluble TNF-alpha receptors in patients with Guillain-Barre syndrome. J Neuroimmunol. 1996;68(1-2): 95-99.
[39] Hartung HP, Reiners K, Schmidt B, et al. Serum interleukin-2 concentrations in Guillain-Barre syndrome and chronic idiopathic demyelinating polyradiculoneuropathy: comparison with other neurological diseases of presumed immunopathogenesis. Ann Neurol. 1991;30(1):48-53.
[40] Sharief MK, McLean B, Thompson EJ. Elevated serum levels of tumor necrosis factor-alpha in Guillain-Barre syndrome. Ann Neurol. 1993;33(6):591-596.
[41] Radhakrishnan VV, Sumi MG, Reuben S, et al. Serum tumour necrosis factor-alpha and soluble tumour necrosis factor receptors levels in patients with Guillain-Barre syndrome. Acta Neurol Scand. 2004;109(1):71-74.
[42] Redford EJ, Hall SM, Smith KJ. Vascular changes and demyelination induced by the intraneural injection of tumour necrosis factor. Brain. 1995;118(Pt 4):869-878.
[43] Oka N, Akiguchi I, Kawasaki T, et al. Tumor necrosis factor-alpha in peripheral nerve lesions. Acta Neuropathol. 1998;95(1):57-62.
[44] Campana WM, Li X, Shubayev VI, et al. Erythropoietin reduces Schwann cell TNF-alpha, Wallerian degeneration and pain-related behaviors after peripheral nerve injury. Eur J Neurosci. 2006; 23(3):617-626.
[45] Zelenka M, Schafers M, Sommer C. Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain. 2005;116(3):257-263.
[46] Korn T, Toyka K, Hartung HP, et al. Suppression of experimental autoimmune neuritis by leflunomide. Brain. 2001;124 Pt 9: 1791-1802.
[47] Zhu J, Bai XF, Hedlund G, et al. Linomide suppresses experimental autoimmune neuritis in Lewis rats by inhibiting myelin antigen-reactive T and B cell responses. Clin Exp Immunol. 1999;115(1):56-63.
[48] Zou LP, Deretzi G, Pelidou SH, et al. Rolipram suppresses experimental autoimmune neuritis and prevents relapses in Lewis rats. Neuropharmacology. 2000;39(2):324-333.
[49] Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411-452.
[50] Philip R, Epstein LB. Tumour necrosis factor as immunomodulator and mediator of monocyte cytotoxicity induced by itself, gamma-interferon and interleukin-1. Nature. 1986;323(6083): 86-89.
[51] Gonzalez-Quevedo A, Carriera RF, O'Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain Barre syndrome. Neurol India. 2009;57(3):288-294.
[52] Shubayev VI, Angert M, Dolkas J, et al. TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol Cell Neurosci. 2006;31(3):407-415.
[53] Weishaupt A, Bruck W, Hartung T, et al. Schwann cell apoptosis in experimental autoimmune neuritis of the Lewis rat and the functional role of tumor necrosis factor-alpha. Neurosci Lett. 2001; 306(1-2):77-80.
[54] Weishaupt A, Bruck W, Hartung T, et al. Schwann cell apoptosis in experimental autoimmune neuritis of the Lewis rat and the functional role of tumor necrosis factor-alpha. Neurosci Lett. 2001; 306(1-2):77-80.
[55] Cheng C, Qin Y, Shao X, et al. Induction of TNF-alpha by LPS in Schwann cell is regulated by MAPK activation signals. Cell Mol Neurobiol. 2007;27(7):909-921.
[56] Hu S, Peterson PK, Chao CC. Cytokine-mediated neuronal apoptosis. Neurochem Int. 1997;30(4-5):427-431.
[57] Farias AS, de la Hoz C, Castro FR, et al. Nitric oxide and TNFalpha effects in experimental autoimmune encephalomyelitis demyelination. Neuroimmunomodulation. 2007;14(1):32-38.
[58] Hartung HP, Jung S, Stoll G, et al. Inflammatory mediators in demyelinating disorders of the CNS and PNS. J Neuroimmunol. 1992;40(2-3):197-210.
[59] Hartung HP, Toyka KV. T-cell and macrophage activation in experimental autoimmune neuritis and Guillain-Barre syndrome. Ann Neurol. 1990;27 Suppl:S57-63.
[60] Zhang J, Dong H, Li B, et al. Association of tumor necrosis factor polymorphisms with Guillain-Barre syndrome. Eur Neurol. 2007; 58(1):21-25.
[61] Pociot F, Briant L, Jongeneel CV, et al. Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol. 1993;23(1):224-231.
[62] Weissensteiner T, Lanchbury JS. TNFB polymorphisms characterize three lineages of TNF region microsatellite haplotypes. Immunogenetics. 1997;47(1):6-16.
[63] Wilson AG, Symons JA, McDowell TL, et al. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A. 1997; 94(7):3195-3199.
[64] Bouwmeester T, Bauch A, Ruffner H, et al. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004;6(2):97-105.
[65] Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003; 114(2):181-190.
[66] Kumpfel T, Hohlfeld R. Multiple sclerosis. TNFRSF1A, TRAPS and multiple sclerosis. Nat Rev Neurol. 2009;5(10):528-529.
[67] De Jager PL, Jia X, Wang J, et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet. 2009;41(7): 776-782.
[68] Baker E, Chen LZ, Smith CA, et al. Chromosomal location of the human tumor necrosis factor receptor genes. Cytogenet Cell Genet. 1991;57(2-3):117-118.
[69] Schall TJ, Lewis M, Koller KJ, et al. Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell. 1990;61(2):361-370.
[70] Chaudhary PM, Eby MT, Jasmin A, et al. Activation of the NF-kappaB pathway by caspase 8 and its homologs. Oncogene. 2000;19(39):4451-4460.
[71] Zhang SQ, Kovalenko A, Cantarella G, et al. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity. 2000; 12(3):301-311.
[72] Hsu H, Shu HB, Pan MG, et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996;84(2):299-308.
[73] Jiang Y, Woronicz JD, Liu W, et al. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Science. 1999; 283(5401):543-546.
[74] Miki K, Eddy EM. Tumor necrosis factor receptor 1 is an ATPase regulated by silencer of death domain. Mol Cell Biol. 2002;22(8): 2536-2543.
[75] Cope AP, Liblau RS, Yang XD, et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med. 1997;185(9):1573-1584.
[76] Kieseier BC, Kiefer R, Gold R, et al. Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system. Muscle Nerve. 2004;30(2):131-156.
[77] Herbein G, Mahlknecht U, Batliwalla F, et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature. 1998;395(6698): 189-194.
[78] Speiser DE, Sebzda E, Ohteki T, et al. Tumor necrosis factor receptor p55 mediates deletion of peripheral cytotoxic T lymphocytes in vivo. Eur J Immunol. 1996;26(12):3055-3060.
[79] Zheng L, Fisher G, Miller RE, et al. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995;377(6547): 348-351.
[80] Bachwich PR, Chensue SW, Larrick JW, et al. Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages. Biochem Biophys Res Commun. 1986; 136(1):94-101.
[81] Lindholm D, Heumann R, Meyer M, et al. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature. 1987;330(6149):658-659.
[82] van Oosten BW, Barkhof F, Truyen L, et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996;47(6):1531-1534.
[83] Deng H, Yang X, Jin T, et al. The role of IL-12 and TNF-alpha in AIDP and AMAN. Eur J Neurol. 2008;15(10):1100-1105.
[84] Weishaupt A, Gold R, Hartung T, et al. Role of TNF-alpha in high-dose antigen therapy in experimental autoimmune neuritis: inhibition of TNF-alpha by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis. J Neuropathol Exp Neurol. 2000;59(5):368-376.
[85] George A, Buehl A, Sommer C. Tumor necrosis factor receptor 1 and 2 proteins are differentially regulated during Wallerian degeneration of mouse sciatic nerve. Exp Neurol. 2005;192(1): 163-166.
[86] Kollias G. TNF pathophysiology in murine models of chronic inflammation and autoimmunity. Semin Arthritis Rheum. 2005; 34(5 Suppl1):3-6.
[87] Aggarwal BB. Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB. Ann Rheum Dis. 2000;59 Suppl 1:i6-16.
[88] Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech. 2000;50(3):184-195.
[89] MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal. 2002;14(6):477-492.
[90] Kurz M, Pischel H, Hartung HP, et al. Tumor necrosis factor-alpha-converting enzyme is expressed in the inflamed peripheral nervous system. J Peripher Nerv Syst. 2005; 10(3):311-318.
[91] Moss ML, Sklair-Tavron L, Nudelman R. Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2008;4(6): 300-309.
[92] Redford EJ, Smith KJ, Gregson NA, et al. A combined inhibitor of matrix metalloproteinase activity and tumour necrosis factor-alpha processing attenuates experimental autoimmune neuritis. Brain. 1997;120(Pt 10):1895-1905.
[93] Newton RC, Solomon KA, Covington MB, et al. Biology of TACE inhibition. Ann Rheum Dis. 2001;60 Suppl 3:iii25-32.
[94] Essayan DM, Huang SK, Kagey-Sobotka A, et al. Differential efficacy of lymphocyte- and monocyte-selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression. J Allergy Clin Immunol. 1997;99(1 Pt 1):28-37.
[95] Souness JE, Griffin M, Maslen C, et al. Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a 'low-affinity' phosphodiesterase 4 conformer. Br J Pharmacol. 1996;118(3): 649-658.
[96] Ohnishi A, Yamamoto T, Her Q, et al. The effect of brain-derived neurotrophic factor on regeneration of nerve fibers after crush injury--morphometric evaluation. J Uoeh. 1996;18(4):261-271.
[97] Abbas N, Zou LP, Pelidou SH, et al. Protective effect of Rolipram in experimental autoimmune neuritis: protection is associated with down-regulation of IFN-gamma and inflammatory chemokines as well as up-regulation of IL-4 in peripheral nervous system. Autoimmunity. 2000;32(2):93-99.
[98] Constantinescu CS, Hilliard B, Lavi E, et al. Suppression of experimental autoimmune neuritis by phosphodiesterase inhibitor pentoxifylline. J Neurol Sci. 1996;143(1-2):14-18.
[99] Rott O, Cash E, Fleischer B. Phosphodiesterase inhibitor pentoxifylline, a selective suppressor of T helper type 1- but not type 2-associated lymphokine production, prevents induction of experimental autoimmune encephalomyelitis in Lewis rats. Eur J Immunol. 1993;23(8):1745-1751.
[100] Kumari M, Cover PO, Poyser RH, et al. Stimulation of the hypothalamo-pituitary-adrenal axis in the rat by three selective type-4 phosphodiesterase inhibitors: in vitro and in vivo studies. Br J Pharmacol. 1997;121(3):459-468.
[101] Pettipher ER, Labasi JM, Salter ED, et al. Regulation of tumour necrosis factor production by adrenal hormones in vivo: insights into the antiinflammatory activity of rolipram. Br J Pharmacol. 1996;117(7):1530-1534.
[102] King RH, Craggs RI, Gross ML, et al. Effects of glucocorticoids on experimental allergic neuritis. Exp Neurol. 1985;87(1):9-19.
[103] Tan XD, Dou YC, Shi CW, et al. Administration of dehydroepiandrosterone ameliorates experimental autoimmune neuritis in Lewis rats. J Neuroimmunol. 2009;207(1-2):39-44.
[104] Matsuki S, Iuchi Y, Ikeda Y, et al. Suppression of cytochrome c release and apoptosis in testes with heat stress by minocycline. Biochem Biophys Res Commun. 2003;312(3):843-849.
[105] Wang J, Wei Q, Wang CY, et al. Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. J Biol Chem. 2004;279(19):19948-19954.
[106] Wang X, Zhu S, Drozda M, et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease. Proc Natl Acad Sci  U S A. 2003;100(18):10483-10487.
[107] Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417(6884):74-78.
[108] Makonkawkeyoon S, Limson-Pobre RN, Moreira AL, et al. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1993; 90(13):5974-5978.
[109] Melchert M, List A. The thalidomide saga. Int J Biochem Cell Biol. 2007;39(7-8):1489-1499.
[110] Kontoyiannis D, Pasparakis M, Pizarro TT, et al. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999;10(3):387-398.
[111] Kontoyiannis D, Kotlyarov A, Carballo E, et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. Embo J. 2001;20(14): 3760-3770.
[112] Loetscher H, Steinmetz M, Lesslauer W. Tumor necrosis factor: receptors and inhibitors. Cancer Cells. 1991;3(6):221-226.
[113] Aderka D, Engelmann H, Maor Y, et al. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors. J Exp Med. 1992;175(2):323-329.
[114] Radhakrishnan VV, Sumi MG, Reuben S, et al. Serum tumour necrosis factor-alpha and soluble tumour necrosis factor receptors levels in patients with Guillain-Barre syndrome. Acta Neurol Scand. 2004;109(1):71-74.
[115] Sharief MK, Ingram DA, Swash M, et al. I.v. immunoglobulin reduces circulating proinflammatory cytokines in Guillain-Barre syndrome. Neurology. 1999;52(9):1833-1838.
[116] Ruiz de Souza V, Carreno MP, Kaveri SV, et al. Selective induction of interleukin-1 receptor antagonist and interleukin-8 in human monocytes by normal polyspecific IgG (intravenous immunoglobulin). Eur J Immunol. 1995;25(5):1267-1273.
[117] Taylor JM, Pollard JD. Soluble TNFR1 inhibits the development of experimental autoimmune neuritis by modulating blood-nerve- barrier permeability and inflammation. J Neuroimmunol. 2007; 183(1-2):118-124.
[118] Bao L, Lindgren JU, Zhu Y, et al. Exogenous soluble tumor necrosis factor receptor type I ameliorates murine experimental autoimmune neuritis. Neurobiol Dis. 2003;12(1):73-81.
[119] Jackson JM. TNF- alpha inhibitors. Dermatol Ther. 2007;20(4): 251-264.
[120] Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000; 356(9227):385-390.
[121] Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum. 2004;50(7):2264-2272.
[122] Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152(6):1304-1312.
[123] Stoll G, Jung S, Jander S, et al. Tumor necrosis factor-alpha in immune-mediated demyelination and Wallerian degeneration of the rat peripheral nervous system. J Neuroimmunol. 1993;45(1-2): 175-182.
[124] Mitoma H, Horiuchi T, Hatta N, et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology. 2005;128(2): 376-392.
[125] Mitoma H, Horiuchi T, Tsukamoto H. Binding activities of infliximab and etanercept to transmembrane tumor necrosis factor-alpha. Gastroenterology. 2004;126(3):934-935.
[126] Rigby WF. Drug insight: different mechanisms of action of tumor necrosis factor antagonists-passive-aggressive behavior? Nat Clin Pract Rheumatol. 2007;3(4):227-233.
[127] Scallon B, Cai A, Solowski N, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002;301(2):418-426.
[128] Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244-279.
[129] Hartung HP, Kieseier BC, Kiefer R. Progress in Guillain-Barre syndrome. Curr Opin Neurol. 2001;14(5):597-604.
[130] Tha-In T, Bayry J, Metselaar HJ, et al. Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol. 2008;29(12):608-615.
[131] Steed PM, Tansey MG, Zalevsky J, et al. Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science. 2003;301(5641):1895-1898.
[132] Szymkowski DE. Creating the next generation of protein therapeutics through rational drug design. Curr Opin Drug Discov Devel. 2005;8(5):590-600.
[133] Zalevsky J, Secher T, Ezhevsky SA, et al. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J Immunol. 2007;179(3): 1872-1883.
 (Edited by Victor M. Arce/Su LL/Song LP)