Mark A. Tepper

Elucidating the mechanism of action of the immunosuppressant 15-deoxyspergualin.

Summary 15-Deoxyspergualin (DSG) is an immunosuppressive agent currently in Phase I/II clinical trials. We have previously shown that DSG specifically interacts with Hsc70, a member of the heat shock protein 70 family. In this article we show that DSG appears to bind either kinetically or to a different site on Hsc70 from that of peptides. In addition, we show that DSG inhibits the localization of Hsp70 into the nucleus in response to heat shock. Finally, data are presented showing that there is a correlation between decreases in the transcription factor nuclear factor kappa B and K light chain expression in response to varying doses of DSG.

15-Deoxyspergualin: A Novel Immunosuppressive Drug with Clinical Potential

The studies discussed in this review suggest that DSG is a potent immunosuppressive agent, with at least some of its activity due to its direct effects on macrophages and B cells. The effects of DSG on macrophages include inhibition of IL-1, chemiluminescence, expression of MHC Class I antigen on the surface, and development of MAF. The agent may well interfere with antigen processing and the discovery of its binding to the heat-shock protein 70 may shed some light on this area. The effects of DSG on B lymphocytes include inhibition of surface Ig expression and B cell differentiation. In addition, however, DSG exhibits some effects on both B and T lymphocytes and is markedly active in blocking both the primary and secondary cytotoxic T cell and antibody-producing cell generation. The agent is relatively nontoxic at the doses in which it exerts these marked effects. Thus, an overall assessment of DSG shows that it may provide immune suppression at levels different from those of immunosuppressive agents already available. Advances in human organ transplantation have for the most part occurred stepwise with the introduction of progressively improved techniques of immunosuppression. Tissue-matching, organ preservation, techniques of transplantation, and surgical post-operative care of organ transplant recipients have all improved over the 30 years since organ transplantation began, but have not been the major factors in the improved survival of both patients and grafts seen at the present time. The initial advance in immunosuppression which made the first organ transplants possible was the finding of the immunosuppressive capabilities of azathioprine (Imuran) and the ability to reverse acute rejection crisis with prednisone. Anti-thymocyte or anti-lymphocyte globulin, introduced in 1966, achieved variable results, with some groups reporting excellent patient and graft survival using this agent. Others using different variations of this drug showed no improvement in results. By the mid-1970s, transplant results had improved at a number of units, with graft survivals of kidney and heart recipients in the 70 percent range at 1 to 2 years. No major progress was reported in most units, however, until the introduction in 1978 of cyclosporine. A major effect of cyclosporine was to create a universal improvement in graft survival in all units surveyed around the world with a 70 to 75 percent one-year cadaver kidney graft survival, representing the basic standard for clinical results.(ABSTRACT TRUNCATED AT 400 WORDS)

Suppression of human anti-mouse antibody response to murine monoclonal antibody L6 by deoxyspergualin: A phase I study

The concept of using monoclonal antibodies (MAbs) to localize and treat human tumors has become a clinical reality over the last few years. Antibodies have been used to modulate the host immune system to activate tumoricidal effector mechanisms and are being used as targeting vehicles for delivery of exogenous cytotoxic molecules such as radioisotopes, chemicals and biologicals. Their ability to selectively target tumor cells also makes them attractive for radioimmunoimaging and for assessing tumor response to therapy1.