Purpose: Because anti-donor alloantibody (alloAb) elaboration is associated with chronic allograft rejection, peri-transplant B cell depletion is being explored to modulate pathogenic alloimmunity. Here, we evaluate an αCD20 agent specifically developed for use in non-human primates to evaluate preemptive B cell depletion in the context of selective αCD28 blockade.

Methods: Cynomolgus monkey MHC-mismatched heterotopic cardiac allograft transplant recipients were treated for 3 months with a selective non-activating αCD28 (FR104, n=12). Five of the 12 additionally received RhαCD20 (Rhesus recombinant IgG; NHP Resource) on d-1 and d21. αCD28 receptor coverage, alloAb production, and B cell phenotypes [naïve (IgD⁺CD27^–), transitional (IgD⁺CD27^–CD38⁺IgM⁺), isotype switched memory (IgD^–CD27⁺), and non-switched memory (IgD⁺CD27⁺)], were monitored by flow cytometry at regular intervals.

Results: 100% CD28 receptor coverage was consistently achieved through d90. With RhαCD20, peripheral blood B cells were reduced to <1% of baseline by d0 (day of transplant), and remained <10% of baseline for >2-3 months. Three of 7 animals treated with αCD28 monotherapy, but none receiving αCD20+αCD28, rejected during αCD28 treatment. In the αCD20-treated animals, recovery in B cell counts to ≥10% of baseline preceded or coincided with detection of anti-donor IgM and IgG alloAb and graft rejection, which occurred consistently by 130d (range 50-144d). In contrast, alloAb elaboration and graft loss were only observed after 150d (range 150-180d) in the four αCD28-treated recipients that did not reject during αCD28 monotherapy treatment. All grafts failed due to CAV in association with alloAb.

Conclusions: Efficient, durable preemptive B cell depletion using RhαCD20 prevents graft rejection during αCD28 treatment, as previously shown in this model in conjunction with CsA and αCD154 regimens. Our observations suggest that B cell depletion may also interfere with emergence of graft-protective immunomodulation that develops in some recipients with αCD28 treatment. Both preemptive B cell depletion and selective non-activating αCD28 blockade deserve further evaluation to prevent pathogenic alloimmunity, alloAb elaboration, and chronic allograft vasculopathy.

CITATION INFORMATION: O'Neill N., Zhang T., Sun W., Braileanu G., Cheng X., Tatarov I., Hassanein W., Habibabady Z., Cerel B., Reimann K., Azimzadeh A., Pierson R. Preemptive B Cell Depletion Modulates Pathogenic Alloimmunity Associated with Selective Non-Activating CD28 Blockade Am J Transplant. 2017;17 (suppl 3).

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