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Tolerance, mixed chimerism, and chronic transplant arteriopathy
P S Russell1, C M Chase, M Sykes
1Department of Surgery, Transplantation Biology Research Center, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA. psrussell@partners.org
Journal of Immunology (Baltimore, Md. : 1950)
|November 8, 2001
Summary
Transplant rejection involves immune responses to donor antigens. This study found that even with induced tolerance, transplanted mouse hearts developed significant vasculopathy, suggesting innate immunity may play a role.
Area of Science:
- Immunology
- Transplantation Biology
- Vascular Biology
Background:
- Chronic transplant rejection is often linked to immune responses against donor-specific incompatibilities.
- Transplant arteriopathy, a form of atherosclerosis, is a common complication of chronic rejection.
Purpose of the Study:
- To investigate the impact of altered immunological responsiveness to donor antigens on the development of arteriopathy in transplanted mouse hearts.
- To explore the role of specific immunological tolerance in preventing or promoting transplant-associated vasculopathy.
Main Methods:
- Induction of specific immunological tolerance via neonatal allogeneic spleen cell administration or adult bone marrow infusion, creating mixed chimerism.
- Assessment of donor-specific skin graft survival, donor cell chimerism, and antibody production in tolerant recipients.
- Histopathological examination of transplanted hearts for vasculopathy, including analysis of cellular infiltrates (T cells, macrophages).
- Evaluation of vasculopathy in recipients with severe combined immunodeficiency (SCID) or RAG1 deficiency, lacking T and B cell responses.
Main Results:
- Both neonatal tolerance and mixed chimerism induction prevented systemic graft-versus-host effects, ensuring graft survival and chimerism without detectable specific antibodies.
- A high incidence of striking coronary artery vasculopathy was observed in tolerant recipients (12/15 neonatal, 15/23 mixed chimeras).
- Isotransplants (genetically identical) showed minimal vasculopathy (2/29), while transplants into immunodeficient recipients (SCID, RAG1(-/-)) still developed significant vasculopathy (16/31).
Conclusions:
- Transplant-associated vasculopathy can develop in the presence of H-2 gene incompatibility even with minimal conventional adaptive immune reactivity.
- Innate immune responses, potentially involving Natural Killer (NK) cell activity, may contribute to the development of arteriopathic lesions in transplanted organs.
- Further research is needed to elucidate the mechanisms of innate immune-driven vasculopathy in transplantation.