Acquisition of Humoral Transplantation Tolerance upon De Novo Emergence of B Lymphocytes

Abstract

A major obstacle to transplantation tolerance is humoral immunity. In this paper, we demonstrate that the intrinsic developmental propensity of the B lymphocyte compartment for acquisition of self-tolerance can be harnessed to induce humoral unresponsiveness to transplanted alloantigens. In the current study, when transitional B cells developed in the presence of donor lymphoid cells, the mature B lymphocyte compartment failed to mount a donor-specific alloantibody response to an organ transplant—despite unrestrained acute T cell-mediated allograft rejection. Specifically, we generated an experimental system wherein a B6 strain B cell compartment developed de novo in the presence of F1 (B6xBALB/c) lymphoid cells and in a T cell-deficient setting. Following establishment of a steady-state B cell compartment, these B6 mice were transplanted with heterotopic cardiac allografts from allogeneic BALB/c donors. The mice were then inoculated with purified syngeneic B6 T cells. As expected, all cardiac allografts were acutely rejected. However, the B lymphocyte compartment of these mice was completely inert in its capacity to form a BALB/c-specific alloantibody response. Using an alloantigen-specific Ig transgenic system, we demonstrated that this profound degree of humoral tolerance was caused by clonal deletion of alloreactive specificities from the primary B cell repertoire. Thus, de novo B cell compartment development at the time of transplantation is of critical importance in recipient repertoire “remodeling” to a humoral tolerant state.

Correlations of lymphocyte subset infiltrates with donor-specific antibodies and acute antibody-mediated rejection in endomyocardial biopsies

“…Recent studies describe an antibody-independent role of B cells due to the capacity of B cells to secrete inflammatory cytokines and chemokines, and participate in antigen presentation and T cell and dendritic cell regulation [24][25][26]. The development of de novo B cell compartment at the time of transplantation is of critical importance in recipient repertoire "remodeling" to a humoral tolerant state [26].…”

“…The development of de novo B cell compartment at the time of transplantation is of critical importance in recipient repertoire "remodeling" to a humoral tolerant state [26].…”

Regulatory B-Cells in Transplantation

“…In a mouse model of a skin-heart transplant, after B-cell reconstitution and rechallenge with alloantibodies, no antibody reaction against the donor was observed [9]. This suggests that the development stage of B-cells in which the encounter with the alloantigen takes place is important for the induction of specific humoral tolerance.…”

“…Depleting B-cells with monoclonal antibodies in the presence of alloantigen to promote donor-specific humoral tolerance has been suggested [9,51]. There are few studies with a limited number of KTR patients.…”

Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans

“…The 3–83 Igi BCR-knock-in mice that express a BCR with dual specificity for H-2K k and H-2K b were used to show the deletional fate of alloreactive B cells in an anti-CD154-induced model of peripheral transplantation tolerance 74 , and that the presence of memory alloreactive B cells prevented the induction of anti-CD154-mediated allograft acceptance 75 . Parsons et al 76 used bone marrow cells from a related 3–83 BCR-Tg mouse to generate mixed bone marrow chimeras, and to show that emerging donor-specific B cells were deleted in the presence of allogeneic bone-marrow cells but acquired an anergic phenotype in the presence of heart allografts. However, limited availability of BCR-Tg mice with allo-MHC specificity and notable caveats of using mice bearing nonphysiological frequencies of monoclonal populations of B cells have hampered the widespread application of this approach for studying the fate of donor-specific B cells in mouse models.…”