Purpose: HSC engraftment is essential for successful bone marrow transplantation, and successful HSC engraftment allows for induction of tolerance to solid organ allografts. Engrafted HSCs are thought to differentiate into donor dendritic cells (DCs) that direct negative selection of anti-donor T cells and/or down-regulate host anti-donor responses. Experimental evidence suggests that chimerism of hematopoietic cells might promote central T cell tolerance and allow for acceptance of an allograft from the donor without the need for immunosuppression. A logical, targeted, approach to enhance HSC engraftment involves blockade of PRRs, known triggers of cellular activation and stress.

Methods: HSCs from WT, or NLRP3 inflammasome component deficient (NLRP3-/-, ASC-/- ), all on a B6 (H-2b) background, were isolated and injected into allogeneic Balb/c (H-2d) mice after preconditioning with sublethal irradiation (300 Rads) and anti-CD8/antiCD40L. Donor cells were tracked by FACS, for H-2Kb congenic markers. T cell proliferation was checked in a MLR reaction.

Results: Disruption of apoptosis-associated speck-like protein containing a CARD (ASC), significantly enhanced allogeneic HSC engraftment. Interestingly, deletion of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome protein did not improve HSC engraftment.

There was also a significant decrease in the ability of ASC-/- T cells to proliferate in response to allogeneic DCs, and conversely a significant defect in the ability of DCs from ASC-/- mice to stimulate allogeneic T cells .

Conclusion: Disruption of the inflammasome coreceptor molecule ASC, but not NLRP3, enhances engraftment of HSCs into complete MHC mismatched hosts, and deletion of ASC in T cells and DCs downregulates alloresponses, suggesting that ASC might be a potential target to improve engraftment of allogeneic HSCs and induce allotolerance.

CITATION INFORMATION: Elahimehr R, Kasimsetti S, Shigeoka A, McKay D. Blockade of the ASC Coreceptor Enhances Hematopoietic Stem Cell Engraftment. Am J Transplant. 2016;16 (suppl 3).

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