Cytokines, anti-cytokine mAbs

Anti-cytokine mAbs in rheumatoid arthritis 452 Anti-adhesion molecule mAbs 454 Anti-T cell mAbs in RA 455... 

To get further insights into the anti-CD3-induced nephrotoxicity, we investigated in a murine model the abihty of anti-CD3 mAb to directly damage native kidneys. For this purpose, we injected mice with the hamster anti-mouse CD3 mAb 145-2C11 [153]. Like OKT3, this mAb is immunosuppressive [154] and first induces a transient release of several cytokines in the circulation, such as IL-2, IL-6, TNF-a, and IFN-y [102, 155, 156]. Histologic analysis revealed signs of tubular ne-... 

The role of cytokines in anti-CD3-mAb-mediated nephropathy was analyzed by pretreating mice with either neutralizing anti-TNF antibodies or mPDS [156]. The histologic lesions and the renal excretion of endopeptidase 24.11 were moderately prevented by anti-TNF antibodies, suggesting the involvement of other mediators, which could act in synergy with TNF-a. In support of this view, steroid pretreatment before anti-CD3 challenge almost completely abohshed IL-2, TNF-a and IL6 release and resulted in preservation of renal histology. 

TNFa is a potent pro-inflammatory cytokine that has been implicated in the pathogenesis of RA (20). In particular, the TNFa transgenic mice, who express hiunan TNFa constitutively in the joint, develop a spontaneous inflammatoiy arthritis resembling RA (21). Treatment vifith anti-TNFa mAb suppresses inflammation in several animal models of RA (22). In RA patients, TNFo can be foimd both in the blood and the joint particularly at the cartilage-pannus junction (23, 24). 

Over the last 30 years, significant scientific advances have elucidated the biochemical processes that result in acute and chronic allergic inflammatory rhinitis. The basic laboratory work on IgE has translated into the cUnical application of anti-IgE MAb as a therapeutic agent for allergic rhinitis. Similar progress has been made with respect to antileukotrienes, PAF inhibitors, a thromboxane-prostanoid receptor antagonist, and inhibitors of important cytokines such as IL4 and IL-5. These advances are expected in the near future to reduce the considerable morbidity that allergic rhinitis patients presently withstand in daily life. 

IL-2 and IL-15, which uses the (3- and y-chains of the IL-2R, have been found in melanoma cells and anti-IL-15 mAbs to inhibit HLA class I expression in these cells. Therefore these cytokines may modify the behavior of both stromal and neoplastic cells inside a tumor. These data may have important implications for our understanding of tumor-host interactions and in future strategies of immunotherapy. When compared with lL-2, which enhances both spontaneous and antigen-induced lymphocyte proliferative responses, IL-15 rarely increases spontaneous lymphocyte proliferation. Thus IL-15 may help to correct the impaired profiferative response of CD4 lymphocytes from HlV-l-infected persons without the mitogenic effect of IL-2, which also may induce HIV-1 expression. "... 

Immunologic Rituximab is a frequent cause of infusion reactions, usually classified as cytokine release syndrome. Whether these reactions are in fact so-called cytokine release syndrome or true type I hypersensitivity responses is not always clear. In an investigation of immxme responses to the mAb in a rheumatoid arthritis patient who experienced two infusion reactions, the patient proved skin test-positive to the mAb and IgE anti-rituximab antibodies were found in the serum. The findings of rituximab-specific IgE antibodies and Th2 cells suggested type I hypersensitivity may be involved in at least some rituximab infusion reactions [195 ]. 

Probably the best studied mAb to CDS in experimental models is the hamster anti-murine CDS mAb 145-2C11 which recognizes an epitope of the epsilon chain in the CDS complex (29). This mAb is a potent immunosuppressive agent in vivo capable of delaying skin allograft rejection to a mean of 32-34 days compared to untreated controls (30). Administration of the first dose of mAb triggers a cytokine release syndrome characterized by the presence of TNF-a. 

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