Regulation of donor specific antibody production

The generation of donor reactive antibodies is a major hurdle in clinical transplantation and are drivers of acute or chronic antibody mediated rejection (ABMR). ABMR is one of the leading causes of renal transplant loss. Current standards of care for ABMR include plasma exchange and or intravenous immunoglobulin, and glucocorticoids, yet no treatment has FDA approval for the treatment of ABMR. Pathogenic donor specific antibodies (DSA) are generated following B cell activation and differentiation into plasmablasts and plasma cells. We have limited ability to target PCBs in transplantation to control humoral rejection, as PCBs do not express CD20 they evade the effects of Rituximab, and plasmapheresis is not a long-term solution. The only current therapy targeting PCBs is Bortezomib but is associated with side effects of neurotoxicity and anemia as reported from phase II and III trials in multiple myeloma, and in kidney transplant patients. Lymphocyte activation gene 3 (LAG3) is a coinhibitory receptor of the immunoglobulin domain superfamily and a homolog of the TCR- coreceptor molecule CD4. Similar to CD4, LAG3 binds MHC-II, alongside other non-classical ligands. LAG3 is expressed by a range of immune cells. Additionally, LAG3 is expressed by B cells, NK cells and pDCs. Most studies have focused on the role of LAG3 on T cells, with recent studies elucidating a mechanisms of T cell inhibition by LAG3. In contrast little is known about LAG3 on antibody responses. Our preliminary experiments indicate that follicular T cells and plasma cells express LAG3 cells following transplantation in a murine kidney transplant model. Use of LAG3 deficient transplant recipients identified LAG3 as a regulator of B cell responses in transplantation as recipient allografts were acutely rejected via ABMR. The rejection was confirmed to be dependent on B cells and not CD8+ T cells following experiments where recipient B cells or CD8+ T cells were depleted. Rejection was not mediated through dysfunction of Tregs as T cell conditional LAG3-/- recipients did not reject their allografts, but had elevated levels of serum DSA. Strikingly, B cell conditional LAG3-/- recipients also did not reject their kidney allografts, despite still producing high levels of serum DSA. Using LAG3 agonistic strategies, we were able to reduce antibody production in vitro, in vivo, and prevent rejection in a robust model of ABMR. The goal of this proposal is to investigate mechanisms of LAG3 mediated regulation of alloantibody responses following kidney transplantation. We hypothesize that LAG3 signaling suppresses both follicular T cells and plasma cells, controlling pathogenic alloantibody responses following kidney transplantation. We will test our hypothesis in two Specific Aims: Aim 1: To investigate the effect of LAG3 signaling on follicular T cell functions and how it influences DSA production. Aim 2: To investigate the effect of LAG3 signaling on plasma cells and how it influences DSA production. Project Number: 1R01AI195504-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Michael Nicosia | Institution: CLEVELAND CLINIC LERNER COM-CWRU, CLEVELAND, OH | Award Amount: $690,359 | Activity Code: R01 | Study Section: Immunobiology of Transplantation and Alloimmunity Study Section[ITA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19550401