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Shaoping Deng,
Daniel J Moore,
Xiaolun Huang,
Moh-Moh Lian,
Muhammad Mohiuddin,
Ergun Velededeoglu,
Major K Lee,
Samsher Sonawane,
James Kim,
Jing Wang, Haiying Chen,
Steven A Corfe,
Christopher Paige,
Mark Shlomchik,
Andrew Caton,
James F Markmann
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ABSTRACT: Selective interference with the CD45RB isoform by mAb (anti-CD45RB) reliably induces donor-specific tolerance. Although previous studies suggest participation of regulatory T cells, a mechanistic understanding of anti-CD45RB-induced tolerance is lacking. We report herein the unexpected finding that tolerance induced by this agent is not established in B cell-deficient mice but can be recovered by preemptive B lymphocyte transfer to B cell-deficient hosts. Using B cells from genetically modified donors to reconstitute B cell-deficient recipients, we evaluate the role of B lymphocyte-expressed CD45RB, T cell costimulatory molecules, and the production of Abs in this novel tolerance mechanism. Our data document an Ab-induced tolerance regimen that is uniquely B lymphocyte-dependent and suggest mechanistic contributions to tolerance development from the B cell compartment through interactions with T cells.
The Journal of Immunology 06/2007; 178(10):6028-32. · 5.79 Impact Factor
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Shaoping Deng,
Daniel J Moore,
Xiaolun Huang,
Mohammad Mohiuddin,
Major K Lee,
Ergun Velidedeoglu,
Moh-Moh Lian,
Meredith Chiaccio,
Samsher Sonawane,
Anton Orlin,
Jing Wang, Haiying Chen,
Andrew Caton,
Robert Zhong,
James F Markmann
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ABSTRACT: Targeting of the CD45RB isoform by mAb (anti-CD45RB) effectively induces donor-specific tolerance to allografts. The immunological mechanisms underlying the tolerant state remain unclear although some studies have suggested the involvement of regulatory T cells (T-regs). Although their generative pathway remains undefined, tolerance promoting T-regs induced by systemic anti-CD45RB treatment have been assumed to originate in the peripheral immune system. We demonstrate herein that separable effects on the peripheral and central immune compartments mediate graft survival induced by anti-CD45RB administration. In the absence of the thymus, anti-CD45RB therapy is not tolerogenic though it retains peripheral immunosuppressive activity. The thymus is required for anti-CD45RB to produce indefinite graft survival and donor-specific tolerance, and this effect is accomplished through thymic production of donor-specific T-regs. These data reveal for the first time an Ab-based tolerance regimen that relies on the central tolerance pathway.
The Journal of Immunology 04/2006; 176(5):2799-807. · 5.79 Impact Factor
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ABSTRACT: While great advances have been made in the success of islet transplantation to cure autoimmune diabetes, this protocol remains limited by our inability to induce donor-specific tolerance within the recipient. The profound resistance of the NOD mouse to tolerance-inducing regimens that are routinely successful in other strains further defines the imposing barriers that must be surmounted. Herein, we have assessed the utility of anti-CD45RB therapy to induce tolerance to allografts in C57BL/6 and NOD-strain mice. We find that, as with other therapies, NOD mice are also resistant to this manipulation, despite robust tolerance induction in the comparison strain. Analysis of cell surface markers revealed a number of changes within the B lymphocyte compartment following contact with antibody and alloantigen in the B6 strain. The absence of reciprocal changes within the NOD lymphocyte compartment suggests that B cells might contribute to the mechanism of action of this therapy and to the resistance to immunological tolerance noted in the NOD strain.
Transplant International 07/2004; 17(5):261-9. · 2.92 Impact Factor
