Cyclosporine (CsA) is a potent immunosuppressive agent which has been utilized to prevent solid organ transplant rejection and Graft versus Host disease following bone marrow transplantation. The precise subcellular mechanism of action of CsA is unclear at present. Recent studies from our laboratory have demonstrated that CsA binds to and inhibits calmodulin, a 17 kD calcium- dependent protein involved in many cellular activities. These data, coupled with increasing evidence of the role of calcium- dependent processes in T lymphocyte function, have led us to hypothesize that CsA inhibition of calmodulin and/or other calcium-dependent proteins may largely explain its immunosuppressive effects of T lymphocytes and possibly macrophages. The studies outlined in this research proposal will directly define the interaction of CsA and its active and inactive derivatives with the calcium-dependent proteins (proteins kinase C, calmodulin, phospholipase A2 and phospholipase C) and their acceptor proteins such as cyclic nucleotide phosphodiesterase. These studies will also define the immunosuppressive effects of a number of classes of calcium-calmodulin antagonists primarily on T lymphocyte subset generation (T helper cytotoxic and suppressor cells). These agents will be analyzed both alone and in combination with CsA. These studies will identify the specific calcium-dependent proteins which interact with CsA and their relative important in the CsA effect on T lymphocytes. These studies will also offer an indication of the relative importance of calcium-dependent processes in general and the calcium-dependent proteins in particular for the function and generation of the various T lymphocyte subsets in the immune response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
2K08CA000958-04
Application #
3079415
Study Section
(SRC)
Project Start
1984-07-01
Project End
1989-06-30
Budget Start
1987-07-10
Budget End
1988-06-30
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Colombani, P M; Bright, E C; Wells, M et al. (1989) Drug-drug interaction between cyclosporine and agents affecting calcium-dependent lymphocyte proliferation. Transplant Proc 21:840-1
Scheibel, L W; Colombani, P M; Hess, A D et al. (1989) Calcium/calmodulin functions in P. falciparum in vitro--implications for antiprotozoal drug design. Prog Clin Parasitol 1:21-56
Colombani, P M; Bright, E C; Hess, A D (1988) Comparison of binding to peripheral blood lymphocytes between active and inactive derivatives of cyclosporine. Transplant Proc 20:46-50
Colombani, P M; Bright, E C; Monastyrskyj, O et al. (1987) Subcellular action of cyclosporine: interaction between CsA and calmodulin antagonists. Transplant Proc 19:1171-4
Hess, A D; Colombani, P M (1987) Mechanism of action of cyclosporine: a unifying hypothesis. Adv Exp Med Biol 213:309-30
Scheibel, L W; Colombani, P M; Hess, A D et al. (1987) Calcium and calmodulin antagonists inhibit human malaria parasites (Plasmodium falciparum): implications for drug design. Proc Natl Acad Sci U S A 84:7310-4
Hess, A D; Colombani, P N (1987) Cyclosporin-resistant and -sensitive T-lymphocyte subsets. Ann Inst Pasteur Immunol 138:606-11
Colombani, P M; Robb, A; Hess, A D (1985) Cyclosporin A binding to calmodulin: a possible site of action on T lymphocytes. Science 228:337-9