Strategies to Inhibit Alloantibody Production in Alloprimed Murine Recipients of Hematopoietic Stem Cell Grafts

Abstract

Alloantibody, not primed T cells, is the major barrier to bone marrow (BM) engraftment in allosensitized mice. We have shown that a single intravenous injection of donor splenocytes, to mimic a blood transfusion, results in high, sustained levels of serum alloantibody sufficient to eliminate donor BM within 3 h, resulting in uniform mortality in lethally irradiated allogeneic recipients. Current studies focused preventing and treating allopriming. Blockade of B cell survival signals with mTACI-Ig pre-and postpriming was ineffective, as was the B cell but not plasma cell depleting anti-CD20 mAb. Germinal center formation inhibition by lymphotoxin-beta receptor-Ig (LbR-Ig) diminished allosensitization, although conditional Prmd1 (Blimp-1) deletion in CD19þ cells was highly effective. By combining anti-CD20 mAb to reduce B cells and LTbR-Ig to diminish the frequency of B cells that could form germinal centers pre-and postpriming, allosensitization was precluded, permitting long-term survival in T-and NK-depleted, irradiated allogeneic recipients, whereas combined therapy postpriming alone was ineffective. As evidence of the critical role of B cells, the proteosomal inhibitor, bortezomib, given unencapsulated or encapsulated, proved ineffective in influencing allosensitization. These data extend our understanding of allopriming and provide a potential therapy for patients at risk for allosensitization and BM graft rejection.Abbreviations: APRIL, a proliferation-inducing ligand; BLIMP-1, B-lymphocyte induced maturation protein-1; BLyS, B-lymphocyte stimulator; BM, bone marrow; BMT, bone marrow transplantation; BTZ, bortezomib; Fl, flox; Ig, immunoglobulin; LTbR-Ig, lymphotoxinbeta receptor-immunoglobulin; MFI, mean fluorescent intensity; (m)TACI, (mouse) transmembrane activator and calcium-modulator and cyclophilin ligand receptor interactor; PB, peripheral blood; PBL, peripheral blood lymphocyte; PC, plasma cell; Prmd1, PR domain containing 1, with ZNF domain; Tfh, T follicular helper cell

The End Is in Sight: Targeting Sensitization in Hematopoietic Cell Transplantation

“…Although GC reactions were disrupted, unaffected extrafollicular and GC-independent memory B cells and plasma cells could have contributed to this outcome. Finally, combining both B cell depletion and LTbR-Ig, the authors demonstrate successful abrogation of both alloantibodies and engraftment failure in sensitized recipients as early as 1 month after sensitization (3). In addition to targeting B cells, this combined approach likely has overarching effects on DC functions and donor reactive T cell responses that remain to be examined in the context of HCT.…”

“…Disrupting follicular dendritic cells networks that support GC reactions using lymphotoxin-beta receptorimmunoglobulin (LTbR-Ig) decreased alloantibodies after sensitization only partially and did not prevent engraftment failure (3). Although GC reactions were disrupted, unaffected extrafollicular and GC-independent memory B cells and plasma cells could have contributed to this outcome.…”