Despite multi-drug prophylaxis, aGVHD affects 20-70% of allogeneic hematopoietic cell transplant (allo-HCT) patients. V-region Immunoglobulin-containing Suppressor of T cell Activation (VISTA), a negative checkpoint regulator expressed on resting nave mouse and human T cells. A single dose of agonist VISTA monoclonal antibody (mAb) on allo-HCT day 0 causes antigen-specific operational tolerance by deletion and anergy in resting nave T cells that have concurrent T cell receptor (TCR) signals and 90-100% long-term survival. VISTA has been linked to induced Treg generation, expansion, stability and maintenance. In acute graft-vs-host disease (aGVHD), agonist mAb increases peripheral Tregs; the extent to which pTregs contribute to operational tolerance will be explored (aim 1A). Limited data exist for aGVHD prevention. Polyclonal CD4 T cells are the dominant aGVHD effectors in MHC disparate aGVHD models and TCR signaling is critical for deletion/anergy; studies are proposed using high affinity donor TCR transgenic and polyclonal CD4 and/or CD8 T cells will assess operation tolerance and long-term survival in MHC and minor antigen disparate models. Tetramers will track polyclonal and monoclonal donor allospecific T cells in agonist mAb treated mice. Frequently used calcineurin inhibitors (CNIs) may alter TCR signals below a threshold needed for agonist mAb effects; testing is required before translation (aim 1C). A unique feature of VISTA is downregulation with T cell activation. Non-alloreactive T cells and alloreactive T cells escaping agonist mAb induced deletion/anergy may permit generation of leukemia-specific T cells (aim 1B). Steroids are first line therapy for aGVHD patients but only half the patients have day 28 complete responses; 1-year survival rate for steroid refractory (SR) aGVHD patients is dismal. In mice and patients, we show myeloid cell infiltration is 2.5-fold higher than T cells in gut, a primal aGVHD organ in SR aGVHD. VISTA is expressed on myeloid cells at >10-fold higher levels than T cells. Agonist mAb inhibits myeloid cell chemotaxis and reprograms inflammatory monocytes/macrophages into anti- inflammatory cells. We hypothesize that agonist mAb reprograming of gut monocytes/macrophages can treat SR aGVHD (aim 2). Our central hypothesis is agonist VISTA mAb has dual uses for aGVHD prevention, inducing T cell operational tolerance, and SR aGVHD therapy, reprogramming myeloid cells to be anti- inflammatory.
Our aims will test the hypotheses that: Operational tolerance induced by agonist mAb allospecific deletion/anergy of donor T cells depends on in vivo Treg induction, permits unaffected T cells to generate leukemia-specific responses, and is subverted by day 0 inflammation or CNIs initiated pre-transplant (aim 1).
In aim 2, we will test the hypothesis that agonist mAb reprograms inflammatory monocytes and macrophages in the gut to be anti-inflammatory and locally release of immune suppressive cytokines, ameliorating SR aGVHD without systemic side-effects of exogenous cytokines. Our studies are foundational for translation of Noelle?s agonist human VISTA mAb for aGVHD prevention and SR aGVHD therapy.
Our team will gain biological insights into immune system control of graft-versus-host disease (GVHD) providing an exciting new approach for GVHD prevention and therapy. Our findings have broad implications for the use of agonist VISTA antibody for hematopoietic stem cell and solid transplantation as well as autoimmunity settings.
