In this competitive renewal of a Clinical Trials in Organ Transplantation consortium funded for >16 years, we will employ our established infrastructure and experience in clinical trials, biomarkers and mechanistic studies to perform a randomized controlled trial (RCT) aimed at individualizing therapy for kidney transplant (KTx) recipients. We propose prospective, multicenter, RCT to test the hypothesis that the HLA-DR/DQ molecular mismatch (eplet, mMM) between donor and recipient reliably stratifies post-transplant risk of graft injury in KTx recipients. To this end, we will determine the utility of HLA-DR/DQ mMM to safely guide tacrolimus (TAC) substitution with abatacept s.c (aim 1), validate HLA-DR/DQ mMM as a prognostic biomarker of primary alloimmunity (aim 2), and determine the utility of non-invasive biomarkers to detect biopsy-proven rejection (BPAR) and monitor the response to BPAR therapy in KTx subjects (aim 3)d. Accompanying mechanistic studies are designed to support and add interpretive value to the proposed clinical trial. Using serially collected and stored PBMC, plasma, serum, urine sediment and supernatant, and biopsy tissue, we will a) test the hypothesis that the degree of HLA DR/DQ mMM determines the size of the donor-reactive CD4+ T cell repertoire, b) test effects of abatacept substitution for TAC on the recipients' immune, c) use state-of-the-art technologies to identify molecular subtypes of graft rejection that could potentially guide novel treatment strategies to eliminate the injury, and d) discern mechanisms linking TAC to kidney dysfunction through molecular analysis of KTx tissue/cells using samples from the RCT in which we substitute TAC with abatacept. We also propose a multisite infectious disease trial concept with an overall objective to interrogate the durability of vaccine-preventable seroprotection across organs and immunosuppression regimens. Together, the work will attempt to validate the predictive utility of HLA-DR/DQ mMM in KTx recipients, determine the safety and efficacy of abatacept as a TAC substitute (hypothesized to be preferentially effective in subjects with low HLA mMM), and document whether and how this change in therapy affects off-target effects associated with CNI. As any transplant center can perform the HLA-DR/DQ mMM biomarker and we designed the proposed study to be informative regardless of outcomes, the work has the potential to have a paradigm- shifting and sustained transformative impact on the clinical care of KTx recipients. Additionally, as we designed accompanying mechanistic studies, using state-of-the-art tools/assays that will delineate the effects of abatacept on the recipients' donor-reactive immune response, the studies will provide mechanistic insights into how abatacept improves outcomes (or why it does not), further enhancing significance.