Long-term allograft survival and tolerance induction by the synergistic activity of malononitrilamides and tacrolimus

Autor: R.R. Bartlett, J.K Lindner, R. Kurrle, H.U. Schorlemmer
Rok vydání: 1998
Předmět:
Zdroj: Transplantation Proceedings. 30:4099-4103
ISSN: 0041-1345
Popis: IN TRANSPLANTATION medicine the combination of agents that separately act on early T-cell and later B-cell functions and on acute and chronic rejection might provide the benefit of a complementary immunosuppressive response. Despite the clinical successes achieved over the past two decades in transplantation, there continues to be a need for new immunosuppressive agents that are less toxic and more effective in down-regulating humoral alloreactivity in presensitized recipients. The novel immunosuppressive malononitrilamides (MNAs) belong to the derivatives of leflunomide’s well-tolerated active metabolite (A77 1726), are chemically unrelated, and distinct in their mode of action to any other immunosuppressant known. The low molecular weight HMR 1279 (C14H11N3O2) and HMR 1715 (C15H11F3N2O2) have been developed in preclinical models of transplantation because they have a shorter half-life in animals and would make dose-adjustment easier in transplant patients. Both MNAs have been shown to bind specifically to dihydro-orotate-dehydrogenase (DHODH) and inhibit de novo pyrimidine biosynthesis, thereby blocking Tand B-cell proliferation and strongly suppressing the IGM and IgG antibody production in vitro. They are able to dose-dependently suppress the proliferation of several immune and nonimmune cell lines. At concentrations that block cell proliferation, the MNAs inhibit DHODH. This antiproliferative effect is consistently antagonized by adding uridine to cell cultures to replenish nucleotide pools. The MNAs inhibit both the cellular and humoral immune response, and they have potent immunosuppressive activity against a variety of experimental autoimmune diseases, primarily reducing autoantibody formation. HMR 1279 and HMR 1715 effectively control graft-versus-host (GvH) diseases in various rodent models, and they can control xenograft survival in hamsterto-rat or mouse-to-rat models. They also were shown to prevent and reverse acute heart and skin allograft rejection, while they were well tolerated in these rodent transplantation studies. Due to the unique pharmacologic profile of the MNAs to inhibit the cellular and humoral immune response and their already described synergistic effects in combination with cyclosporine (CyA) to prolong alloand xenograft survival, we tested the combination therapy of HMR 1279 or HMR 1715 and FK 506 in view of their individual and distinct immunosuppressive actions in rat skin allotransplantation models using different donor-recipient strain combinations.
Databáze: OpenAIRE
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