Blockade of CD40-mediated signaling is sufficient for inducing islet but not skin transplantation tolerance
Phillips, Nancy E. ; Markees, Thomas G. ; Mordes, John P. ; Greiner, Dale L. ; Rossini, Aldo A.
Citations
Student Authors
Faculty Advisor
Academic Program
Document Type
Publication Date
Keywords
Antibodies, Blocking
Antibodies, Monoclonal
Antigen-Presenting Cells
Antigens, CD40
Antigens, CD80
CD4-Positive T-Lymphocytes
CD40 Ligand
Combined Modality Therapy
Graft Enhancement, Immunologic
Graft Survival
Injections, Intraperitoneal
Islets of Langerhans Transplantation
Lymphopenia
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Radiation Chimera
Receptors, Interleukin-2
Signal Transduction
Skin Transplantation
Species Specificity
Tissue Donors
Transplantation Conditioning
*Transplantation Tolerance
Life Sciences
Medicine and Health Sciences
Subject Area
Embargo Expiration Date
Link to Full Text
Abstract
Treatment of mice with a single donor-specific transfusion (DST) plus a brief course of anti-CD154 mAb to block CD40-mediated signaling uniformly induces donor-specific transplantation tolerance. Survival of islet allografts in treated mice is permanent, but skin grafts eventually fail unless recipients are thymectomized. The nature of the cellular mechanisms involved and the basis for the difference in survival of islet vs skin allografts are not known. In this study, we used CD40 knockout mice to investigate the role of CD40-mediated signaling in each component of the tolerance induction protocol: the DST, the graft, and the host. When CD40-mediated signaling was eliminated in only the DST or the graft, islet allografts were rapidly rejected. However, when CD40 signaling was eliminated in the host, approximately 40% of the islet allografts survived. When CD40 signaling was eliminated in the DST, the graft, and the host, islet grafts survived long term (>84 days), whereas skin allografts were rapidly rejected ( approximately 13 days). We conclude that transplantation tolerance induction in mice treated with DST and anti-CD154 mAb requires blockade of CD40-mediated signaling in the DST, the graft, and the host. Blockade of CD40-mediated signaling is necessary and sufficient for inducing islet allograft tolerance and is necessary but not sufficient for long-term skin allograft survival. We speculate that a requirement for regulatory CD4(+) T cells in skin allograft recipients could account for this differential response to tolerance induction.
Source
J Immunol. 2003 Mar 15;170(6):3015-23.