Natural killer (NK) cells are effector cells of the innate immune system that can lyse target cells without prior sensitization, and have an important role in host defense to pathogens and transformed cells. NK cell function is controlled by a balance of negative and positive signals transmitted via germ-line encoded inhibitory and activating receptors. Although the concept of "missing-self" would suggest NK cells could target foreign allografts, the prevailing dogma has been that NK cells are not active participants in the mechanisms that culminate in graft rejection. Recent studies, however, challenge this conclusion and instead implicate NK cells in both acute and chronic allograft rejection. Quite paradoxically, NK cells have also been shown to facilitate tolerance to an allograft. To reconcile these disparate observations we hypothesized that NK cells, through expression and function of activating receptors, regulate other cells of the immune system especially dendritic cells (DC). Indeed we have demonstrated that DC- mediated activation of NK cells is dependent upon signaling through the NKp46 activation receptor. The goal of this exploratory/developmental proposal is to determine how NK interactions regulate the adaptive immune response after transplantation. We propose two integrated Specific Aims: 1) determine the phenotypic and functional features of NK cells after transplantation and 2) determine how NKp46 contributes to the function of NK cells post-transplant, to test our hypothesis that NKp46 is important in regulating NK-mediated immune functions post-transplant. Our innovative study will have important implications in designing strategies to prevent graft rejection and promote tolerance to an allograft.

Public Health Relevance

Natural killer (NK) cells are effector cells of the innate immune system that can lyse target cells without prior sensitization. Recent studies by our lab and others support that NK cells have a paradoxical role in transplantation with strong evidence supporting the role of NK cells in both graft rejection and graft tolerance. We propose to examine the functions of NK cells after transplantation with the goal of developing strategies to improve outcomes for recipients of solid organ allografts.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI104230-02
Application #
8717580
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nabavi, Nasrin N
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Hadad, Uzi; Martinez, Olivia; Krams, Sheri M (2014) NK cells after transplantation: friend or foe. Immunol Res 58:259-67