Central memory stem-cell like cTFH contribution to durable DSA responses and chronic ABMR after kidney transplantation

About This Grant

ABSTRACT Solid organ transplantation has proven effective at extending and improving the quality of life of patients with end-stage organ failure-associated diseases. However, the long-term outcomes after solid organ transplantation (Tx) are suboptimal, with only 60% graft survival by 10 years post-Tx due to chronic rejection (CR). Donor- specific anti-HLA antibodies (DSA) and antibody-mediated rejection (ABMR) are among the most important causes of CR, but the immune mechanisms that dictate which DSA+ABMR patients fair well and which are refractory to treatments and progress to CR and graft loss are still not understood. Therefore, there is a high priority to decipher the immune mechanisms responsible for this heterogeneous clinical behavior, and to identify novel targeted strategies to overcome these unwanted outcomes. We have recently discovered that unlike DSA+ABMR KTx patients with better clinical outcomes, those patients that progressed to CR and graft loss preferentially expanded a unique, previously not described central memory (CM) stem-like cTFH subset, that was highly correlated with durable DSA of IgG3 isotype, activated memory B (memB) cells and plasma blasts (PB), as well as with graft injury and graft loss post-KTx. Based on these novel observations we hypothesize that when present and significantly expanded, stem-like cTFH cells proliferate, self-renew and support a potent, durable humoral response, leading to more aggressive ABMR. We further postulate that persistence of stem-like cTFH contributes to the development of CR and graft loss. Therefore, we will aim to (1) Decipher the longitudinal (pre- Tx, 1, 3, 12, 36 mo) differentiation fate, function, allo-specificity, transcriptomic profiles of stem-like TFH (2) Define signaling and metabolic characteristics linked to the stability and function of stem-like cTFH cells (3) Determine the relationship between tissue-infiltrating stem-like TFH cell profile during chronic DSA+ABMR and subsequent kidney allograft loss. We will also assess whether we can disrupt stem-like TFH generation or drive these cells to become terminally exhausted. We believe this proposal is innovative because it investigates the concept of cTFH stemness fueling humoral rejection, a concept that has not been explored in human organ transplantation. The proposal is significant because (i) understanding the biology and clinical implications of stem-like cTFH cells would provide valuable mechanistic insights into how to optimally monitor to risk-stratify patients with DSA+ABMR and predict poor allograft outcomes; (ii) identify biologic or pharmacologic tools to disrupt or re-program stem-like cTFH leading to novel therapeutic opportunities for CR; (iii) open new avenues of research applicable to recipients of other types of organ transplants (e.g. heart and lung), or to patients with autoimmunity.