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Tolerance to antigen-presenting cell-depleted islet allografts is CD4 T cell dependent
1Barbara Davis Center for Childhood Diabetes/University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|March 11, 1999
Summary
Pancreatic islet allografts pretreated in high oxygen accept indefinitely by depleting antigen-presenting cells (APCs). This induces donor-specific tolerance, mediated by CD4+ T cells, not CD8+ T cells, via indirect antigen presentation.
Area of Science:
- Immunology
- Transplantation Biology
- Cellular Immunology
Background:
- Pancreatic islet transplantation is a potential therapy for type 1 diabetes.
- Graft rejection is a major obstacle, often mediated by antigen-presenting cells (APCs) and T cell responses.
- Understanding tolerance mechanisms is crucial for improving transplant outcomes.
Purpose of the Study:
- To investigate the induction of long-term allograft acceptance and donor-specific tolerance.
- To elucidate the role of antigen-presenting cells (APCs) and T cell subsets in transplant tolerance.
- To explore the mechanisms of peripheral alloantigen presentation in the absence of costimulation.
Main Methods:
- Pretreatment of pancreatic islets in 95% oxygen culture to deplete graft-associated APCs.
- Transplantation of APC-depleted allografts into immunocompetent recipients.
- Assessment of allograft acceptance and development of donor-specific tolerance.
- Adoptive transfer experiments using immune-deficient SCID mice.
- Analysis of CD4+ and CD8+ T cell responses in tolerant recipients.
Main Results:
- APC-depleted islet allografts achieved indefinite acceptance in immunocompetent recipients.
- A state of donor-specific tolerance developed, characterized by resistance to donor APC-induced rejection.
- Tolerance could be adoptively transferred to SCID mice, confirming active immune regulation.
- Tolerant CD8+ T cells collaborated with naive CD4+ T cells to reject grafts, while tolerant CD4+ T cells did not collaborate with naive CD8+ T cells.
- MHC class I+, II- islet allografts induced changes in CD4+ T cells, not CD8+ T cells.
Conclusions:
- Graft persistence alone, after APC depletion, is sufficient to induce donor-specific tolerance.
- The tolerant state is mediated by CD4+ T cells, suggesting a shift in their responsiveness.
- Tolerance likely occurs via the indirect pathway of donor antigen presentation to CD4+ T cells, involving host MHC class II molecules.