Distinct mechanisms for the induction and maintenance of allograft tolerance with CTLA4-Fc treatment.
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.
Tran
H M
HM
National Pancreas Transplant Unit, Westmead Hospital, New South Wales, Australia.
Nickerson
P W
PW
Restifo
A C
AC
Ivis-Woodward
M A
MA
Patel
A
A
Allen
R D
RD
Strom
T B
TB
O'Connell
P J
PJ
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D007108:Immune Tolerance; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007668:Kidney; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D009928:Organ Specificity; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D000069594:Abatacept