ABSTRACT
A murine CTLA4/Fc gamma2a heavy chain (mCTLA4-Fc) chimeric fusion molecule was used in B6AF1 recipients of BALB/c pancreatic islet allografts to study the induction and maintenance of tolerance following inhibition of the CD28-B7 pathway for T cell activation. Donor-specific tolerance was achieved by administering 100 microg of mCTLA4-Fc on alternate days for 14 days (8 total doses) or a single 500 microg dose of mCTLA4-Fc on day 2 after transplant. Tolerance was mediated by long-lived peripheral lymphocytes and showed features of organ and alloantigen specificity. Whereas tolerance could not be established in allograft recipients receiving simultaneous mCTLA4-Fc and rIL-2, previously tolerant animals did not reject their grafts when given IL-2, suggesting that the induction and maintenance phases of tolerance were distinct and separate. The maintenance of donor-specific tolerance was an active immunologic process that was CD4+ T cell dependent and could be adoptively transferred to naive lymphocytes, but could not be explained by apoptosis or deletion of alloreactive T cells. Although an IL-2-sensitive mechanism such as anergy may contribute toward the induction of tolerance, its maintenance involves active suppression.
Subject(s)
Antigens, Differentiation/pharmacology , Graft Enhancement, Immunologic/methods , Graft Rejection/prevention & control , Immunoconjugates , Immunosuppression Therapy/methods , Immunosuppressive Agents/pharmacology , Islets of Langerhans Transplantation/immunology , Transplantation, Homologous/immunology , Abatacept , Adoptive Transfer , Animals , Antigens, CD , CTLA-4 Antigen , Graft Survival , Immune Tolerance , Immunoglobulin Fc Fragments , Immunosuppressive Agents/antagonists & inhibitors , Interleukin-2/pharmacology , Kidney , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Organ Specificity , Recombinant Fusion Proteins/pharmacology , Recombinant Proteins/pharmacology , Skin Transplantation/immunology , Transplantation, HeterotopicSubject(s)
Azathioprine/therapeutic use , Cyclosporins/therapeutic use , Graft Survival , Kidney Transplantation/physiology , Adult , Creatinine/metabolism , Cyclosporins/adverse effects , Follow-Up Studies , Humans , Kidney Transplantation/immunology , Prednisolone/therapeutic use , Retrospective StudiesABSTRACT
Six patients with renal failure were given a single oral dose (250 mg) of diflunisal. In contrast to the acyl glucuronide, the phenolic glucuronide and sulphate conjugates showed the capacity to accumulate in plasma, suggesting that systemic instability of the acyl glucuronide contributes, via hydrolysis, to plasma concentrations of diflunisal itself. Although earlier studies in renal failure patients have almost certainly underestimated diflunisal clearance (by overestimation of plasma diflunisal concentrations through unrecognized acidic hydrolysis of diflunisal sulphate during analysis), the present results suggest that the reported decrease in clearance was not attributable only to this analytical artifact.
