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NIH grant 1R01AI192944-01A1: Central memory stem-cell like cTFH contribution to durable DSA responses and chronic ABMR after kidney transplantation
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: DIANA M METES. Award: $750787.
Start: 2026-07-23T00:00:00.
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.document fetched 2026-08-02 08:24