CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment.
Sensitization to donor Ags is an enormous problem in clinical transplantation. In an islet allograft model, presensitization of recipients through donor-specific transfusion (DST) 4 wk before transplantation results in accelerated rejection. We demonstrate that combined DST with anti-CD154 (CD40L) therapy not only prevents the deleterious presensitization produced by pretransplant DST in the islet allograft model, it also induces broad alloantigen-specific tolerance and permits subsequent engraftment of donor islet or cardiac grafts without further treatment. In addition, our data strongly indicate that CTLA4-negative T cell signals are required to achieve prolonged engraftment of skin allograft or tolerance to islet allograft in recipients treated with a combination of pretransplant DST and anti-CD154 mAb. We provide direct evidence that a CD28-independent CTLA4 signal delivers a strong negative signal to CD4+ T cells that can block alloimmune MLR responses. In this study immune deviation into a Th2 (IL-4) response was associated with, but did not insure, graft tolerance, as the inopportune timing of B7 blockade with CTLA4/Ig therapy prevented uniform tolerance but did not prevent Th2-type immune deviation. While CTLA4-negative signals are necessary for tolerance induction, Th1 to Th2 immune deviation cannot be sufficient for tolerance induction. Combined pretransplant DST with anti-CD154 mAb treatment may be attractive for clinical deployment, and strategies aimed to selectively block CD28 without interrupting CTLA4/B7 interaction might prove highly effective in the induction of tolerance.
Zheng
X X
XX
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Markees
T G
TG
Hancock
W W
WW
Li
Y
Y
Greiner
D L
DL
Li
X C
XC
Mordes
J P
JP
Sayegh
M H
MH
Rossini
A A
AA
Strom
T B
TB
D000069594:Abatacept; D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D018122:B7-1 Antigen / Q000378:metabolism; D001803:Blood Transfusion; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D003131:Combined Modality Therapy; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates; D015847:Interleukin-4 / Q000096:biosynthesis; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects / Q000276:immunology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D015290:Second Messenger Systems / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D014019:Tissue Donors
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D015847:Interleukin-4; D000069594:Abatacept