Acute and chronic graft-versus-host disease (GHVD) remain a significant cause of morbidity and mortality following allogeneic bone marrow transplant (BMT). Although there have been recent advances in treatment and prevention of GVHD, significant problems remain with these approaches. We have used thalidomide, a potent non-toxic immunosuppressant, to treat acute and chronic GVHD. In a rat major mismatch BMT model, 22 of 23 animals with severe established acute GVHD responded to thalidomide therapy. Of 42 animals receiving thalidomide prophylactically, only 8 developed mild GVHD and all of these responde to continued therapy. Eleven of 11 animals with chronic GVHD responded to thalidomide with one responding animal dying of an apparent viral infection. We propose to develop these studies with goal of introducing the drug clinically. For both prophylaxis and treatment of acute and chronic GVHD, transplants will be performed to address the maximally severe acute or chronic GVHD treatable with thalidomide, the optimal length of therapy, the optimal dosing frequency, and combination therapy with CsA or methylprednisolone. To help study thalidomides mechanism of action, we have developed a fluorescent thalidomide derivative (FT) which is more soluble than native thalidomide. FT binds primarily to T lymphocytes with a small avidly binding bright population and a larger less avidly binding dim population. A similar picture of bright and dim populations is seen with a fluorescent dansylated CsA; these population as well as unsorted cells have been extensively characterized in our laboratory. We propose to carry out similar studies using the FT to characterize each of the three lymphocyte populations which bind to FT. Each cell population will be characterized as to phenotype; response to alloantigen, mitogens, IL-2 and viral antigen; ability to induce cytotoxic and suppressor cells by alloantigen IL-2 production in response to alloantigen or mitogen; NK activity; and stimulatory activity. The similarities and differences between the responses seen with CsA and thalidomide will be explored as they may offer clues or the basic immunoregulatory mechanism for the induction of tolerance.
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