Allogeneic cell and tissue transplants nearly always evoke B cell responses ascertainable by detecting donor-specific antibodies (DSA) in the circulation of the recipient. DSA are not universally detected after clinical organ transplants however either because the responses are suppressed by immune therapeutics or because DSA are absorbed to the graft.

We recently found that nearly all kidney transplant recipients develop donor-specific B cell responses ascertained by ELISPOT, using donor cells as target. We reasoned that whether and how donor-specific B cell responses change during the ensuing months could offer a window onto alloimmunity and graft well being. Between 3 and 6 months after transplantation, the total number B cells in blood decreased and the frequency of B cells secreting IgM specific for donor cells (donor-specific ASC) decreased by 20-80%. In recipients that maintained healthy grafts, the number of donor-specific IgG ASC varied considerably from 0-50/10⁴ B cells and always remained below 50/10⁴ B cells during the ensuing 6 months. In contrast, two subjects who later developed rejection exhibited no decrease in donor-specific IgM ASC and the frequency of IgG ASC was >90/10⁴ B cells at 3M and 6 M after transplantation. Single donor-specific B cell Ig (heavy and light chain) sequencing revealed that one rejecting subject had profoundly greater frequency of mutations versus germline in Ig V regions compared to recipients with healthy grafts (p<0.0001). The presence of highly mutated Ig V region genes in anticipation of rejection is consistent with donor-specific actions of B cells and T cells and suggests these responses could offer an early clue to emergence of rejection and injury. Perhaps more important, the findings reveal a significant temporal dissociation between alloimmune response of B cells (and presumably T cells) on the one hand and the detection of DSA in the blood and acute rejection on the other. This dissociation might reflect an underappreciated impact of immunosuppression on B cell functions, allowing expansion but not terminal differentiation and antibody secretion. Alternatively, this dissociation might reflect accommodation of the grafts (i.e. resistance to injury) for a period of time and the possibility in some cases loss of accommodation rather than de novo immunity underlies rejection.

CITATION INFORMATION: Cascalho M, Farkash E, Adam L, Samaniego M, Platt J. Donor-Specific B Cell Responses: Predicting the Future of Kidney Transplants. Am J Transplant. 2017;17 (suppl 3).

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