Allograft, rejection lymphocyte activation

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. 

Clinical pharmacology Basiliximab is a chimeric (mouse/human) interleukin-2 receptor antagonist. It is directed against the interleukin-2 receptor-alpha chain (CD25) on activated T-lymphocytes, and is a potent inhibitor of interleukin-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. Another anti-CD25 monoclonal antibody, dacUzumab (Zenapax), has the same indication as basiliximab. 

Bishop DK, Shelby J, Eichwald EJ. 1992. Mobilization of T lymphocytes following cardiac transplantation. Evidence that CD4- positive cells are required for cytotoxic T lymphocyte activation, inflammatory endothelial development, graft infiltration and acute allograft rejection. Transplantation. 53 849-857. 

Inhibits IL-2 mediated activation of lymphocytes, a critical pathway in the cellular immune response involved with allograft rejection... 

Both basiliximab and daclizumab exert their immunosuppressive effect by specifically binding to the alpha chain (CD25) on the surface of activated T-lymphocytes (see Fig. 87-1). Binding of either basilixmab or daclizumab to the lL-2 receptor prevents lL-2-mediated activation and proliferation of T cells, a critical step in clonal expansion of T cells and the development of allograft rejection. Saturation of the lL-2 receptor occurs rapidly and confers immunosuppressive effect immediately. ... 

Natural killer (NK) cells and cytotoxic T lymphocytes (CTL) are the primary line of defense against viruses and other intracellular pathogens in the immune system. The cytotoxic lymphocytes recognize infected host cells and kill them with the help of the pore-forming protein perforin and by proteolytic events carried out by members of the granzyme family of serine proteases. Although an essential component of immunity under normal conditions, aberrant cytotoxic lymphocyte activity has been associated with autoimmune disorders such as rheumatoid arthritis, diabetes, or allograft rejection [65],... 

Humoral immunity results from the interactions of antigen, macrophages, helper T-cells and B-cells the latter which produces the immunoglobulins antibodies. Cellular Immunity is a function of a number of cell types identified as macrophages, killer cells, and T-cells (l3miphocytes) of which there are functional subpopulations of lymphocytes. The evidence suggesting an effect on cellular Immunity by Se is supported by dinitrochlorobenzene (DNCB) hypersensitivity experiments, allograft rejection times, impaired microbicidal activity, insensitivity of lymphocytes to Se deprivation and carcinostatic activity. 

The receptor for interleukin-2 consists of a molecular complex of three chains termed a (CD25), 8 (CD122), and y (CD132). The a chain is specific for the IL-2 receptor complex whilst the p and y chains are also found in the receptors for other cytokines. The IL-2Ra subunit is only expressed on activated and not resting T cells. Monoclonal antibodies targeting the a subunit can therefore selectively impair T lymphocytes participating in allograft rejection. 

Immunosuppression and Antiinflammatory Effects In addition to its ability to suppress myometrial and endometrial prostaglandin formation, progesterone suppresses T-lymphocyte proliferation, interleukin-8 synthesis, and increases prostaglandin dehydrogenase activity, all of which contribute to preventing maternal rejection of the implanting conceptus (an allograft). 

Smdies in the 1970s showed that cyclosporin inhibits humoral immunoreactions, and that it had a selective effect on T-cell dependent immunoreactions and that its effect was reversible. Cyclosporin is considered to interfere with the process for primary T-cell activation. In this way the formation of T-effector cells, cytotoxic T-lymphocytes or killer lymphocytes, which have the dominant function in cell mediated immune reactions like rejecting an allograft in transplantation surgery and delayed hypersensitivity reaction, is prevented. 

The fact that M-T7 binds not only to IFN-y from rabbit but also to chemokines from various species has allowed its use as a vCKBP in mouse models. The ability of low amounts of recombinant M-T7 protein to attenuate restenosis after balloon angioplasty in rats has been described to be similar to that of the M3 and 35-kDa proteins, as mentioned before. Whether this effect is due to direct inhibition of chemokine activity is not dear at present [25]. Using a rat renal allograft model, chronic rejection was attenuated by M-T7 protein, with significant reduction in tubular and glomerular atrophy, scarring and lymphocyte infiltration [52]. 

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