Function Blocking or Depleting Antilymphocyte Antibodies

Antibodies that react with T cell surface structures and deplete or inhibit T cells are used to treat acute rejection episodes. One widely used antibody is a mouse monoclonal antibody called OKT3 that is specific for human CD3. Polyclonal rabbit or horse antibodies specific for a mixture of human T cell surface proteins, so-called antithymocyte globulin, have also been in clinical use for many years to treat acute allograft rejections. These anti-T cell antibodies deplete circulating T cells either by activating the complement system to eliminate T cells or by opsonizing them for phagocytosis. T cells that escape elimination by OKT3 probably do so by endocytosis ("modulation") of CD3 off their surface, but such cells may be rendered nonfunctional.

Monoclonal antibodies are now in clinical use that are specific for CD25, the a subunit of the IL-2 receptor. These reagents presumably prevent T cell activation by blocking IL-2 binding to activated T cells and IL-2 signaling.

Another monoclonal antibody in use in clinical transplantation is a rat IgM specific for CD52, a cell surface protein expressed widely on most mature B and T cells whose function is not understood. Anti-CD52 was originally developed to treat B cell malignant neoplasms, and it was found to profoundly deplete most peripheral B and T cells for many weeks after injection into patients. In current trials, it has been administered just before and early after transplantation, with the hope that it may induce a prolonged state of graft tolerance as new lymphocytes develop in the presence of the allograft.

The major limitation to the use of monoclonal or poly-clonal antibodies from other species is that humans given these agents produce anti-immunoglobulin (Ig) antibodies that eliminate the injected foreign Ig. For this reason, human-mouse chimeric ("humanized") antibodies (e.g., against CD3 and CD25), which are less immunogenic, have been developed.

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