*Purpose: Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5-/- mice transplanted with complete MHC mismatched kidney allografts and are required for rejection of the grafts between days 18 and 30 post-transplant. Acute antibody-mediated rejection (AMR) also requires NK cell activation to proliferate and express effector functions within the graft. Depletion or inactivation of graft infiltration NK cells results in long-term survival of kidney allografts despite high DSA titers.

*Methods: Since NK cell homeostasis and proliferation are dependent on IL-15, we then tested the impact of anti-CD122 mAb to inhibit IL-15 signaling on kidney allograft survival and NK cell activation within A/J kidneys transplanted to B6.CCR5-/- recipients.

*Results: On day 15, graft-infiltrating NK cell activation to proliferate and express CD107a was equivalent within allografts in control and anti-CD122 mAb treated B6.CCR5-/- recipients and was accompanied with similar graft expression of transcripts associated with NK cell, including SH2D1B1 and IFN-g. In contrast to lack of efficacy for NK cells, anti-CD122 mAb was a very effective inhibitor of memory T cell activation within allografts. Despite the inability to inhibit NK cell activation in kidney allografts, anti-CD122 mAb treatment of B6.CCR5-/- recipients extended survival of 50% (n = 5) of the allografts to between days 55 and 120, with an overall median survival time of 58 days. However, kidney allografts from anti-CD122 mAb- and control- treated recipients exhibited intense C4d deposits in peritubular capillaries indicating no histopathologic difference in graft injury.

*Conclusions: Overall, the results suggest that strategies inhibiting recruitment and activation of T cells in kidney allografts may not be effective in inhibiting activation of kidney allograft-infiltrating NK cells during ABMR.

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