Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic transplantation. cGVHD pathophysiology involves cooperation between T follicular helper cells (TFHs) and germinal center B cells (GCBs), allo- and autoantibody depositions in cGVHD tissues, and fibrosis. We evaluated human CD19–directed chimeric antigen receptor (CAR19) T cell therapy in a clinically relevant murine cGVHD model with bronchiolitis obliterans syndrome (BOS). Although CD8+ CAR19 T cells effectively reduced peripheral B cell and GCB frequencies, pulmonary function was unimproved. In contrast, a single infusion of CAR19 CD4+ regulatory T cells (Tregs) mitigated ongoing pulmonary disease and modulated germinal centers (GCs) associated with reduced TFH frequencies compared with control Tregs but without measurable B cell depletion. Compared with EGFR Treg infusion, mice receiving CAR19 Tregs exhibited enhanced suppression of B cell activation and preserved splenic architecture, and CAR19 Treg infusion provided greater opportunities for interaction with CD19+ B cells at the B cell follicle boundary zones. Taken together with the absence of detectable B cell cytolysis, these findings were most consistent with GC suppression rather than B cell depletion as the dominant mechanism. Overall, our findings suggest that CAR19 Tregs represent a promising and safe cGVHD/BOS therapeutic strategy, offering immunosuppressive benefits and improved disease outcomes that may be more limited with CD8+ CAR19 T cell treatment.
Sujeong Jin, Michael C. Zaiken, Cameron McDonald-Hyman et al.· JCI Insight· 0 citations
Dendritic cells are a rare lineage, consisting of cDC1, cDC2, and the scarce (< 0.3% of blood) DC3. Uniquely, DC3s share monocyte and cDC2 features, marked by co-expression of CD1c and CD14. They promote Th1 and Th17 cells, associate with autoimmunity, and induce CD8+CD103+ tissue-resident memory T-cells that may exacerbate disease. Contrarily, DC3s can be immunosuppressive in a tumor microenvironment. This duality could provide an immunotherapy platform if sufficient-numbers can be obtained.
HSPCs were generated from iPSCs via embryoid bodies; HSPCs were cultured for 2 weeks on murine MS5 stromal cells with SCF, FLT3L, and ascorbic acid. To induce regulatory iDC3s (iDC3regs), CD1c+ isolated cells were treated for 24hrs with CHIR99021 (Wnt agonist), L-kyneurine, retinoic acid and IFNγ, IL-10, and/or TGFβ (γ10β), the latter tested alone and in combination. Suppressive function was measured via AlloMLRs.
iDC3s emerged with a fold-increase of 1096±123 iDC3s per iPSC in 4 maturation states: CD45RA+CD14- (immature), CD45RA-CD14-, CD45RA-CD14+ CD163-, and CD14+CD163 + (mature). Isolated CD1c+ iDC3s cultured with GM-CSF, known to support DC3s, not FLT3L, gradually promoted maturation to a CD14+CD163+ over 3 days. γ10β-iDC3regs were most suppressive, mediated through PDL1 and IDO1. Interestingly, γ10β rapidly induced two states: CD14+CD163- and CD14+CD163+ that resisted inflammatory exposure (TNF+/IL1β/PGE2, LPS, CpG, R848, or GMCSF/IL4). Bulk RNA-seq of these populations is underway to define the regulatory profile and to compare public DC3 datasets. Studies in humanized mouse graft-versus-host disease models will test iDC3regs in vivo regulatory capacity; Studies examining tumor antigen-loaded and activated iDC3s will test their anti-tumor potential.
We demonstrate efficient generation of iDC3s, define their developmental trajectory, and regulatory potential. These findings reveal how DC3s operate across disease contexts.
Kidz1stFund, P01CA065493-28
Transplantation Immunology (TRAN)
Jordan Fink, Ke Yao, Lie Ma et al.· Journal of Immunology· 0 citations
The clinical successes of chimeric antigen receptor (CAR) T cells represent a major shift in immunotherapy. However, there is also increasing emphasis on potential long-term effects of CAR T cell therapy, especially using preclinical xenogeneic models. It has been previously demonstrated that only naïve, and not memory, peripheral blood human T cells can mediate a rapid and acute xenogeneic graft-versus-host disease (xenoGVHD). Here, we demonstrate that simply by altering the donor T cells in the process of generating CAR T cells, in which they are all memory phenotype, that the xenoGVHD outcome was markedly altered. Following tumor clearance with CAR T cell administration, we observed a significantly delayed (up to 200 days post-transfer with some donors) occurrence of lethal xenoGVHD, marked by profound scleroderma and multi-organ pathology consistent with chronic, not acute, GVHD. Notably, this novel chronic xenoGVHD occurred in the absence of B cells, which are classically associated with mediating chronic GVHD pathology. TCR-repertoire constriction during disease and the lack of disease using MHCI/II double-knockout NSG recipient mice confirmed the observed pathology was xenoGVHD and mediated by human-TCR:murine-MHC interactions. Interestingly, despite the consistent expansion of CAR-positive T cells during early tumor-clearance, a later emergence of CAR-negative populations during xenoGVHD also resulted. Our findings highlight xenoGVHD as a problem that makes long-term assessment of CAR T efficacy or toxicity highly problematic in xenograft models due to the artefact of xenoreactivity which is not representative of autologous clinical usage, and the profound effect that T cell alterations have in GVHD pathophysiology.
Wahed A. Firoz, Michael K. Sheng, Pedro Ruivo et al.· Blood Advances· 0 citations
Genetic Id2 loss uncouples Tfh differentiation from effector activity, positioning Id2 inhibition as a novel therapeutic strategy to selectively disrupt pathogenic Tfh-GCB crosstalk in cGVHD.
Yujie Zhao, Eun Ko, Cameron McDonald-Hyman et al.· Journal of Immunology· 0 citations
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