Kidney transplantation elicits powerful B cell responses, which generate antibodies specific for the transplant donor. Donor-specific antibodies can cause acute and chronic rejection and sometimes graft failure. However, donor-specific antibodies are sometimes detected in recipients who lack any evidence of rejection. In this setting, donor-specific antibodies appear to evoke resistance to immune and inflammatory injury instead of rejection. The pathways that enable tissues and organs to accommodate to immunity and inflammation have been studied extensively. But, how a B cell response generates accommodation instead of rejection is not known. The proposed research will address this overarching question in kidney transplant recipients who are tested for donor-specific antibodies and undergo three protocol biopsies during the first year. As a first objective, B cell responses specific for kidney transplant donors will be identified by testing for donor-specific antibodies in blood; but, also by determining the frequency and isotype of donor-specific antibody-secreting cells in blood (because donor-specific antibodies can be substantially absorbed by functioning organ grafts). B cell responses will be interpreted in the light of findings in protocol biopsies to help determine whether a response reflects accommodation or rejection. As a second objective, frequency of mutations in Ig variable region genes and the avidity and range of specificities of the encoded antibodies from donor-specific B cells in accommodation and rejection will be compared. The results of this project will indicate whether accommodation is a common outcome of kidney transplantation. Further, distinct facets of B cell responses in accommodation versus rejection could point to novel approaches to assessing risk and even new targets for biological intervention in transplantation, cancer and other conditions.