Fty720

FTY720 is the first agent in a new class of small molecules, sphingosine 1-phosphate receptor (S1P-R) agonists. It is a prodrug that reduces recirculation of lymphocytes from the lymphatic system to the blood and peripheral tissues, including inflammatory lesions and organ grafts.

Antibodies

Both polyclonal and monoclonal antibodies against lymphocyte cell-surface antigens are widely used for prevention and treatment of organ transplant rejection. Monoclonal reagents have overcome the problems of variability in efficacy and toxicity seen with the polyclonal products, but they are more limited in their target specificity. First-generation murine monoclonal antibodies generally have been replaced by newer chimeric or humanized monoclonal antibodies that lack antigenicity, have prolonged half-lives, and can be mutagenized to alter their affinity to Fc receptors. Both polyclonal and monoclonal products have a place in immunosuppressive therapy (Figure 52-2).

antithymocyte globulin Antithymocyte globulin is a purified gamma globulin from the serum of rabbits immunized with human thymocytes.

Mechanism of Action

Antithymocyte globulin contains cytotoxic antibodies that bind to CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45, and HLA class I and II molecules on the surface of human T lymphocytes. The antibodies deplete circulating lymphocytes by direct cytotoxicity (both complement and cell-mediated) and block lymphocyte function by binding to cell surface molecules involved in the regulation of cell function.

Therapeutic Uses Antithymocyte globulin is used for induction immunosuppression, although the only approved indication is in the treatment of acute renal transplant rejection in combination with other immunosuppressive agents. Antilymphocyte-depleting agents (thymoglobulin, atgam) are thought to improve graft survival. A course of antithymocyte-globulin treatment often is given to

Myeloma cell culture

HPFTrig-

loma Cells

Immunization

HPRT+lg+

Spleen/Lymph Node Cells

Fusion in polyethylene glycol

Expand hybridoma, test supernatant

I Flask

Freeze hybridoma for future use

Selection of hybrid cells in HAT medium and clone ^

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