Title

Blockade of CD40-mediated signaling is sufficient for inducing islet but not skin transplantation tolerance

UMMS Affiliation

Department of Medicine, Division of Diabetes; Department of Medicine, Division of Endocrinology and Metabolism

Date

3-11-2003

Document Type

Article

Subjects

Animals; 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

Disciplines

Life Sciences | Medicine and Health Sciences

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.

Rights and Permissions

Citation: J Immunol. 2003 Mar 15;170(6):3015-23.

Related Resources

Link to Article in PubMed

Journal Title

Journal of immunology (Baltimore, Md. : 1950)

PubMed ID

12626555