CTLA4 Signals Are Required to Optimally Induce Allograft Tolerance with Combined Donor-Specific Transfusion and Anti-CD154 Monoclonal Antibody Treatment

Content Provider	Scilit
Author	Zheng, Xin Xiao Markees, Thomas G. Hancock, Wayne W. Li, Yongsheng Greiner, Dale L. Li, Xian Chan Mordes, John P. Sayegh, Mohammed H. Rossini, Aldo A. Strom, Terry B.
Copyright Year	1999
Description	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.
Ending Page	4990
Page Count	8
Starting Page	4983
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.162.8.4983
Journal	The Journal of Immunology
Issue Number	8
Volume Number	162
Language	English
Publisher	The American Association of Immunologists
Publisher Date	1999-04-15
Access Restriction	Open
Subject Keyword	Cell Tissue Engineering Dst with Anti Cd154
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology