Early allogeneic immune modulation after establishment of donor hematopoietic cell-induced mixed chimerism in a nonhuman primate kidney transplant model.

Autor:	Little CJ; Department of Surgery, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States.; Department of Surgery, University of Washington School of Medicine, Seattle, WA, United States., Kim SC; Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States., Fechner JH; Department of Surgery, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States., Post J; Department of Surgery, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States., Coonen J; Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States., Chlebeck P; Department of Surgery, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States., Winslow M; Department of Surgery, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States., Kobuzi D; Department of Surgery, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States., Strober S; Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, United States., Kaufman DB; Department of Surgery, University of Wisconsin School of Medicine & Public Health, Madison, WI, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jan 22; Vol. 15, pp. 1343616. Date of Electronic Publication: 2024 Jan 22 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1343616
Abstrakt:	Background: Mixed lymphohematopoietic chimerism is a proven strategy for achieving operational transplant tolerance, though the underlying immunologic mechanisms are incompletely understood. Methods: A post-transplant, non-myeloablative, tomotherapy-based total lymphoid (TLI) irradiation protocol combined with anti-thymocyte globulin and T cell co-stimulatory blockade (belatacept) induction was applied to a 3-5 MHC antigen mismatched rhesus macaque kidney and hematopoietic cell transplant model. Mechanistic investigations of early (60 days post-transplant) allogeneic immune modulation induced by mixed chimerism were conducted. Results: Chimeric animals demonstrated expansion of circulating and graft-infiltrating CD4+CD25+Foxp3+ regulatory T cells (Tregs), as well as increased differentiation of allo-protective CD8+ T cell phenotypes compared to naïve and non-chimeric animals. In vitro mixed lymphocyte reaction (MLR) responses and donor-specific antibody production were suppressed in animals with mixed chimerism. PD-1 upregulation was observed among CD8+ T effector memory (CD28-CD95+) subsets in chimeric hosts only. PD-1 blockade in donor-specific functional assays augmented MLR and cytotoxic responses and was associated with increased intracellular granzyme B and extracellular IFN-γ production. Conclusions: These studies demonstrated that donor immune cell engraftment was associated with early immunomodulation via mechanisms of homeostatic expansion of Tregs and early PD-1 upregulation among CD8+ T effector memory cells. These responses may contribute to TLI-based mixed chimerism-induced allogenic tolerance. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Little, Kim, Fechner, Post, Coonen, Chlebeck, Winslow, Kobuzi, Strober and Kaufman.)
Databáze:	MEDLINE
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