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Prevention of chronic rejection and graft arteriosclerosis by tolerance induction
M S Orloff1, E M DeMara, M L Coppage
1Department of Surgery, University of Rochester School of Medicine and Dentistry, New York 14642.
Abstract:
Chronic rejection is a major cause of graft failure in solid organ transplants after the first year. A characteristic lesion in a variety of chronically rejecting organs is a fibrointimal proliferative arteriosclerosis. It has been speculated that approaches to tolerance induction may be effective in obviating not only acute, but also chronic, rejection. A picture of chronic rejection develops naturally in heart grafts transplanted from the Lewis-to-F-344 strain of rat. We examined whether tolerance induction by bone marrow transplantation and development of hematopoietic chimerism or tolerance induction by intrathymic inoculation of alloantigen could effectively prevent chronic rejection in an established model of chronic rejection. Bone marrow chimeras were developed in F-344 hosts by transplantation of T cell-depleted allogeneic marrow (TCD A BMT). Another set of F-344 hosts was inoculated with intrathymic allogeneic bone marrow cells. Heart grafts in these animals demonstrated tolerance for 120 days after transplantation. Control F-344 animals treated with a short course of cyclosporine consistently developed chronic rejection by 120 days following heart transplantation. Strikingly absent from the tolerant animals was any sign of graft arteriosclerosis, which was demonstrated in the vast majority of control animals. Analysis of cytokine mRNA profiles at 30 days following heart transplantation demonstrated differences between control and tolerant animals. These results suggest that tolerance induction can effectively prevent chronic rejection.
Insights
Tolerance induction strategies, including bone marrow transplantation and intrathymic inoculation, prevented chronic rejection and graft arteriosclerosis in heart transplant models. These findings highlight the potential of tolerance to overcome long-term transplant failure.
Area of Science:
- Transplantation immunology
- Graft rejection mechanisms
- Immunological tolerance
Background:
- Chronic rejection is a leading cause of solid organ transplant failure beyond the first year.
- Fibrointimal proliferative arteriosclerosis is a hallmark lesion in chronically rejecting organs.
- Tolerance induction strategies are being explored to prevent both acute and chronic rejection.
Purpose of the Study:
- To investigate the efficacy of tolerance induction in preventing chronic rejection.
- To assess the impact of bone marrow transplantation (BMT) and intrathymic (IT) inoculation on chronic rejection.
- To evaluate the prevention of graft arteriosclerosis in a rat heart transplant model.
Main Methods:
- Established a chronic rejection model using Lewis-to-F-344 rat heart grafts.
- Induced tolerance via T cell-depleted allogeneic bone marrow transplantation (TCD A BMT) or IT inoculation of alloantigen.
- Monitored graft survival and presence of arteriosclerosis for 120 days.
- Analyzed cytokine mRNA profiles at 30 days post-transplantation.
Main Results:
- Tolerance induction via BMT or IT inoculation resulted in sustained heart graft acceptance for 120 days.
- Tolerant animals showed a complete absence of graft arteriosclerosis.
- Control animals treated with cyclosporine developed chronic rejection and arteriosclerosis by 120 days.
- Distinct cytokine mRNA profiles were observed between tolerant and control groups.
Conclusions:
- Tolerance induction effectively prevents chronic rejection and associated graft arteriosclerosis.
- BMT and IT inoculation are viable strategies for inducing long-term transplant tolerance.
- Targeting tolerance mechanisms may offer a novel approach to improve long-term transplant outcomes.