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Interleukins is a family of cytokine immune system signaling molecules produced when body is affected by microbial infection by foreign bodies. Interleukin 2 is one amongst the family of interleukins which is a hormone like mediator involved in cell mediated immunity. IL-2 binds to IL-2 receptors produced by lymphocytes to mediate its effects on the human body.
IL-2 AND CELL MEDIATED IMMUNITY
When the foreign antigen binds to T-cell receptor, IL-2 and IL-2 receptor are secreted. This interact to initiate survival, growth, differentiation of cytotoxic T cells through expression of specific genes (Stern etal., 1986; Beadling et al., 1993; Beadling et al., 2002).
Interleukin signaling plays an crucial role in cell mediated immunity which enables to study primary T cell responses (Kaliannan et al., 2001). IL-2 as a growth factor amplifies lymphocyte responses and clinical uses of IL-2 includes in AIDS and Cancer patients by enhancing T cell immunity (Brad et al., 2004).
Il-2 is responsible for immunologic memory, T-Regs production and development whose main function is in recognition of self antigens and prevention of auto-immunity.
( Sakaguchi et al., 1995; Thornton et al., 1998; Thornton et al., 2004).They also facilitate the proliferation of immunoglobulins and reduces population of self reactive T-cells (Waldmann et al.,1999; Waldmann et al.,2006).
The major role of interleukins is in autoimmune diseases by suppressing the immune system either by decreasing the production of IL-2 by activated T-cells or by blocking IL-2R signaling (Waldmann et al.,1999; Waldmann et al.,2006).
IMMUNOSUPRESSANTS- A285 : (ESTABLISHED)
A-285 (BTP) through calcineurin independent mechanism, inhibits NFAT activity. Srerine/Threonine phosphotase calcineurin and its substrate NFAT which is calcium dependent are inhibited by the drugs of this class. Cyclosporine and tarcolimus are some of the examples of this class which are widely used for organ transplantation by immunosuppression (Birsan et al., 2004).These drugs are accompanied by many side effects like nephrotoxicity and neurotoxicity which may be caused due to inhibition of calcineurin in other cells which are not immune (Birsan et al., 2004).
BTP compounds act by blocking IL-2 gene transcription and mainly act at NFAT nuclei. And does not effect transcription factors associated with it. They also act by regulating calcium ion flow intracellulary Birsan et al., 2004). Although they are widely used, the direct target is yet to be identified.
MERITS: Though the target of action is unidentified, these BTP drugs are used widely in organ transplantation in vivo and illustrates the exact value of A-285 needed for cytokine production useful to evaluate pharmacodynamic effects.
IMMUNOSUPRESSANTS- MACROLIDES (SANGLIFEHRIN A): (IN DEVELOPMENT)
Sanglifehrin A is a novel immunosuppressant and belongs to class of macrolides. It reacts with cyclophilin A and inhibits peptidyl prolyl isomerase activity. Its effects are independent of cyclophilin binding and do not act by inhibiting the phosphotase activity of calcineurin (Gerhard et al., 2001). When compared to other immunosuppressive drugs like CsA and FK506, they do not act by inhibiting T-cells at transcription stage or by secretion but act at a later stage by blocking IL-2 proliferation identical to rapaporine
Actions of Sanglifehrin A:
• SFA inhibits isomerase activity by binding to CypA: SFA inhibited the isomerase activity and proved to be more potent than CsA, other immunosuppressive agents of the same class (Fischer et al.,1989; Takahashi et al., 1989). Studies also revealed that SFA permeation into the cells is more than CsA. Inhibition of isomerase activity leads to suppression of T-cell proliferation at a later stage (Gerhard et al., 2001).
• Inhibition Of Proliferation of Activated T cells: SFA inhibited the proliferation of T-cells cloned with IL-2 and thus suppressed the action of alloantigen stimulated human T-cells (Gerhard et al., 2001).
• Effects of SFA on Cytokine Production: SFA did not affect IL-2 secretion or IL-2 transcription by PMA/PHA stimulation. On the other hand, CsA prevented the IL-2 transcription. Th1 and Th2 production was proved to be reduced by both SFA and CsA with the same potency (Gerhard et al., 2001).
• Dependence of activity on binding to Cyclophilin: Experiments revealed that SFA does not act by binding to Cyclophilin molecules when tested with MLR cultures (Gerhard et al., 2001).
• Effects on targets of known Immunosuppressants: These experiments were done to elucidate exact mechanism of action and the results proved that SFA does not act on any of the targets of known immunosuppressants. Some of the targets tested were FKB12, binding site of FK506 and rapamycin. Others included calcineurin, IMPDH and DHODH.
All these results revealed that this novel immunosuppressive agent acts by entirely different mechanism, which is yet to be tested but has got inhibitory effects on proliferation of T-cells at G1 phase (Zhang et al., 2001) and mitogen activated B-cells.
The results obtained by experimental models suggest that SFA is novel group of immunosuppressants whose mechanism of action is yet to be researched. The ability of this class of immunosuppressants to inhibit proliferation and the relative competition of binding sites with that of CsA could form a potential area of research, digging new targets for treatment.