Role of FK778 Alone or in Combination with Tacrolimus or mTOR Inhibitors as an Immunomodulator of Immunofunctions: In Vitro Evaluation of T Cell Proliferation and the Expression of Lymphocyte Surface Antigens

Abstract

We evaluated the in vitro capacity of FK778, alone or in combination with other immunosuppressive drugs: Tacrolimus (TRL); Sirolimus (SRL), Everolimus (EVL), to inhibit clonal expansion of Tlymphocytes and expression of lymphocyte-activation surface antigens; secondly, we compared the immunosuppressive potential of FK778 combined with TRL, SRL and EVL with the same combinations using Mycophenolic acid (MPA) as antimetabolite. Lymphocyte proliferation was assessed by 3H_ Thymidine incorporation, in whole blood cultures stimulated with ConA. The effect of FK778 on alloresponse was evaluated by MLC and the expression of lymphocyte surface antigens by cytometry. FK778, TRL, SRL and EVL showed a high in vitro capacity to inhibit lymphocyte proliferation in a concentration-dependent way. Combinations of FK778 with TRL, SRL, or EVL presented an additive effect, especially FK778+TRL. Similar inhibition capacity of the clonal expansion was observed, when FK778 was combined with TRL, SRL or EVL, respecting the same combinations but using MPA instead of FK778. In addition, FK778 inhibited the expression of lymphocyte surface antigens involved in activation, co-stimulatory and apoptosis signals. In conclusion, FK778 inhibits the proliferative response induced by mitogeneic and allogeneic stimuli and the expression of surface antigens. Combinations of FK778 with TRL or mTOR inhibitors presented an additive effect and their action on T cell proliferation was similar to that of combinations with MPA. Since FK778, TRL and mTOR inhibitors present different action mechanisms and involve different cellular targets, these combinations may help prevent episodes of allorejection in organ transplants. FK778 and mTOR inhibitors may represent an alternative treatment for patients with renal failure.Over the past two decades many immunosuppressive drugs, such as calcineurin inhibitors (cyclosporine, tacrolimus), antimetabolites (azathioprine, mycophenolate mofetil), mTOR inhibitors (sirolimus, everolimus), and monoclonal antibodies to T lymphocytes (basiliximab, daclizumab, CD3) have been approved for clinical use in the prevention of graft rejection in solid organ transplants.Though notable progress has been achieved in short-term graft survival rates and in the prevention of acute rejection by specific combinations of these immunosuppressive agents, long-term outcomes of

Involvement of NK Cells against Tumors and Parasites

“…Recently, we found that BALB/c mice infected with E. granulosus respond by producing serum MCP-1 as early as 10 days post infection and we determined the serum MCP-1 and MIP-2 levels as indicators for the inflammatory process (39)(40)(41)(42). Other studies have demonstrated that mice infected orally with T. spiralis larvae develop quantitative and functional changes in the peritoneal macrophage population (43,44). These macrophages inhibit DNA synthesis of syngeneic and allogeneic tumor cells and kill EL-4 tumor cells, properties attributed to activated macrophages.…”