. Our goal is to develop new therapies for chronic GVHD (cGVHD). Our preclinical data led to 5 drug trials (1 FDA approved) in this grant period. Since most steroid-refractory cGVHD patients showed partial responses, new strategies based on deeper mechanistic insights are needed. We first showed that germinal centers (GCs) produce pathogenic Ab in cGVHD, supported by T follicular helper (Tfh) and Th17 and inhibited by T follicular regulatory (Tfr) cells. We discovered that cGVHD is restrained by donor bone marrow (BM)-derived Tfrs that have a unique phenotypic and transcriptomic signature, which may impact approaches to increase Tregs and Tfrs. Our data suggest niche cytokines/molecules supporting activated Tregs in the BM may optimize Tfrs. GC cells express PD-1. Strikingly, PD-1 blockade was effective in treating cGVHD; Tfhs were decreased and Tfrs increased, extending our findings that PD-1 inhibits Tfr generation and function. Dr. Sharpe generated mice with PD-1 immunotyrosine-based ITIM and ITSM mutations. PD-1 KO and ITSM, but not ITIM, mutant donor T cells caused high lethality, which may be due to higher T cell expansion or Tfh generation. Our cellular analyses suggest non-redundant functions in controlling Tfh and Tfr generation and function; thus, PD-1 ITSM and the ITIM signaling motifs may play distinct roles in different T cell subsets and cGVHD. Tregs and Teffector cells can express PD-1 and CD112R co-inhibitory receptors. CD112Rpos vs neg Tregs are more suppressive (Proj 2) and CD8 exhausted cells are CD112Rhi (Proj 1). CD101 is highly expressed on terminally exhausted CD8 cells (Proj 1). CD101pos vs neg Tregs are more potently suppressive and can control autoimmunity. We observed CD112R and CD101 are more highly expressed on BM vs splenic Tregs. As many Tfrs are from donor BM in our cGVHD model, BM CD112R+ or CD101+ Tregs may be key Tfr sources. We hypothesize that donor Treg site of origin controls different cGVHD phases and PD-1/CD112R or CD101 synergy is key in regulating GC facilitator and suppressor balance.
Our aims will test the hypotheses that: 1. cGVHD severity is regulated by the nature of PD-1 signals in cells contributing to the GC response. 1A will test the hypotheses that inducible conditional PD-1 deletion in donor BM B cells or Tregs will decrease GC B cells and increase Tfr function, while donor T cell graft conditional PD-1 deletion in T cells or Tregs will increase pathogenic cells and cGVHD. 1B will test the hypotheses that PD-1, ITSM, or ITIM motifs have distinct functions that regulate cGVHD dependent on target cells and signaling pathways engaged early or later in cGVHD. 2. The net effects of Tfh and Tfr donor origin/function and novel inhibitory receptors (CD112R; CD101) regulate cGVHD. 2A will examine contribution of GC populations on cGVHD progression; 2B will test the hypothesis that BM Tregs are functionally distinct, denoted by CD112R or CD101, and examine their individual effects and crosstalk with PD-1 to identify mechanisms that control cGVHD that may lead to new cGVHD therapeutics.
Our goal is to develop clinically relevant therapies to prevent and treat chronic graft-versus-host disease, a major source of morbidity and mortality after allogeneic hematopoietic stem and progenitor cell transplantation (HSPCT). In so doing, the outcome of HSPCT in treatment or malignant and non-malignant disorders can be improved. Moreover, the potential life-saving benefits of this procedure can be extended to other patient populations not routinely treated with HSPCT due to concerns for complications.
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| Porichis, Filippos; Hart, Meghan G; Massa, Alexandra et al. (2018) Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells. J Immunol 201:971-981 |
| LaFleur, Martin W; Muroyama, Yuki; Drake, Charles G et al. (2018) Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol 200:375-383 |
| Chaudhri, Apoorvi; Xiao, Yanping; Klee, Alyssa N et al. (2018) PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface. Cancer Immunol Res 6:921-929 |
| Ahn, Eunseon; Araki, Koichi; Hashimoto, Masao et al. (2018) Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci U S A 115:4749-4754 |
| Wu, Yongxia; Schutt, Steven; Paz, Katelyn et al. (2018) MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood 131:1974-1986 |
| Gartlan, Kate H; Bommiasamy, Hemamalini; Paz, Katelyn et al. (2018) A critical role for donor-derived IL-22 in cutaneous chronic GVHD. Am J Transplant 18:810-820 |
| Hippen, Keli L; Loschi, Michael; Nicholls, Jemma et al. (2018) Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease. Front Immunol 9:57 |
| Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848 |
| Owen, David L; Mahmud, Shawn A; Vang, Kieng B et al. (2018) Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis. J Immunol 200:3926-3933 |
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