Anti’human immunosuppressive

Daclizumab Zenapax (Roche) Humanized anti-CD25 Immunosuppressant (renal transplantation)... 

Nizet Y, et al (2000). The experimental (in vitro) and clinical (in vivo) immunosuppressive effects of a rat IgG2b anti-human CD2 mAb, LO-CD2a/BTI-322. Transplan-tat. 69(7) 1420-1428. 

Humanized recombinant anti-IL-2 receptor antibodies (Basiliximab, Simulect , and Daclizumab Zenapax ). These antibodies bind with high affinity to the IL-2 receptor on T-lymphocytes and prevent activation and clonal expansion of anti-allograft T-lymphocytes by endogenous IL-2. They are used to prevent kidney allograft rejection. The main side effect is immunosuppression. 

Corticosteroids synthesized by the adrenal gland are mineralocorticoids and GC. Min-eralocorticoids regulate fluid and electrolyte balance by affecting ion transport in the kidney. Cortisol, the primary circulating GC in most species (including humans), has many activities, including resistance to stress, regulation of intermediary metabolism, and immunosuppressive and anti-inflammatory effects. GC synthesis and secretion is... 

The anti-inflammatory and immunosuppressive effects of glucocorticoids are largely due to the actions described above. In humans, complement activation is unaltered, but its effects are inhibited. Antibody production can be reduced by large doses of steroids, although it is unaffected by moderate doses (eg, 20 mg/d of prednisone). 

When injected, azathioprine (Imuran) is rapidly converted to 6-mercaptopurine. The half-life of azathioprine after intravenous injection is 10 to 20 min, and that of 6-mercaptopurine is somewhat longer. The cytotoxic activity of these thiopurines is due to the conversion of mercaptopurine to 6-thiouric acid, a noncarcinostatic metabolite. This action is thought to block the excess synthesis of inosinic acid from its precursors, glutamine and phosphoribosylpyrophosphate. In addition, unlike cyclophosphamide, azathioprine is a potent anti-inflammatory substance that can cause a reduction in the number of monocytes and neutrophils at inflammatory sites. Antibody responses are also inhibited by azathioprine. Studies in humans have shown that azathioprine decreases the y-globulin and antibody levels, thus influencing IgG rather than IgM production. This makes azathioprine an effective immunosuppressant in the early phases of immune responses. It is less effective or completely ineffective in altering either the effector phase or already established reactivities. 

Treatment with available anti-TN F-a inhibitors can be associated with the development of antibodies to the administered biologies [10]. The incidence is reported to be higher in patients receiving infliximab (13 to 60%), the chimeric monoclonal antibody containing a murine variable region, compared with the incidences reported for the fusion protein etanercept (<5 %) or the fully human antibody, adalimumab (-12% as monotherapy). The observed incidence of antibody formation is reduced by concomitant immunosuppressive therapies, such as methotrexate. Lower efficacy and higher incidences of infusion-related reactions have been reported in antibody-positive patients receiving infliximab [80]. 

CDw52, a 21- to 28-kDa phosphatidylinositol-linked glycoprotein of unclear function, is widely expressed on the cell surface of both B and T lymphocytes (187). Anti-CDw52 mAbs include CAMPATH-1 and its humanized version CAMPATH-1H (187-188). CAMPATH-IH has been evaluated in multiple clinical trials, in which it has shown anticancer efficacy against a variety of lymphoid neoplasms (188-190). However, CAMPATH-IH also induced rapid depletion of both B cells and T cells, resulting in potentially profound immunosuppression (191). 

Natalizumab (Tysabri), an anti-a4 integrin monoclonal antibody approved for the treatment of multiple sclerosis, was recently withdrawn from the market temporarily due to cases of progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system associated with immunosuppression [32], These cases highlight our incomplete understanding of the immune system and the translation of preclinical results to humans. 

The human experience was not unlike that of the anti-TNFs with respect to an approximate 3- to 3.5-fold higher rate of lymphoma in the intended population (patients with RA) who are at higher risk for the development of lymphoma or lung cancer, particularly those with highly active disease. Similar is the statement that the role of the particular product and the development of human malignancies is not known or fully understood. There is also the added precaution to lessen the putative risk in patients to avoid use with other immunosuppressive agents. 

As a worst-case scenario the possibility exists to break natural tolerance to human Fc and lead to the formation of anti-Fc antibodies, in vivo, due to the presentation of such a high local concentration of Fc domain epitopes to various components of the cellular immune system. As a result, the generation and function of endogenous immunoglobulins could be negatively affected by the presence of these circulating antibodies (immunosuppression). 

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