The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft-versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects from GVHD by modulating alloreactive T cell immunity. However, many factors may influence alloreactive T cell responses in the host undergoing allo-HSCT, including the interaction of alloreactive T cells with both donor and recipient hematopoietic cells and host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Interferons (IFNs), including type I IFNs and IFN-γ, primarily produced by monocytes, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and histone modifications, are important to regulate IFNs’ production and function during GVHD. In this review, we discuss recent findings from preclinical models and clinical studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, and further discuss pharmacological approaches that modulate epigenetic effects in the setting of allo-HSCT.

Management of relapsed cutaneousT‐Celllymphoma following allogeneic hematopoietic stem cell transplantation: Review with representative patient case

“…Interferon‐alpha and interferon‐gamma are two such agents that enhance the immunologic antitumor response by stimulating CD8 + and natural‐killer T cells 23 . CD8 + T cells contribute to the pathogenesis of GVHD, and interferons have a well‐documented risk of GVHD 24–26 . However, stimulation of CD8 + T cells may also augment the antitumor function of the grafted lymphocytes and, as our case demonstrates, interferons can therefore be useful in some patients with low GVHD risk.…”

“…23 CD8 + T cells contribute to the pathogenesis of GVHD, and interferons have a well-documented risk of GVHD. [24][25][26] However, stimulation of CD8 + T cells may also augment the antitumor function of the grafted lymphocytes and, as our case demonstrates, interferons can therefore be useful in some patients with low GVHD risk. Similarly, topical toll-like receptor agonists such as imiquimod and resiquimod, which trigger endogenous interferon production, have been associated with GVHD-like skin conditions.…”

“…Moreover, transplanted immune cells may directly attack tumor cells in what is termed a graft‐versus‐lymphoma (GVL) effect. Several studies have described encouraging long‐term outcomes with allo‐HSCT in high‐risk, younger CTCL patients with good performance status who have achieved complete remission or minimal residual disease at time of transplant 2–33 …”

CARs: a new approach for the treatment of autoimmune diseases

“…Graft-versus-host disease (GvHD): GvHD is a major complication of allogeneic bone marrow transplantation (alloBMT) and donor lymphocyte infusion, and it is mainly caused by donor T cells (Zhao et al, 2021a). MacDonald et al evaluated the therapeutic effects of CAR-Tregs targeting human leukocyte antigen (HLA)-A2, a commonly mismatched alloantigen in transplantation, on GvHD by infusing HLA-A2-positive peripheral blood mononuclear cells (PBMCs) into NSG mice and cotransferring HLA-A2 CAR-Tregs into these mice.…”

Graft-versus-Host Disease Modulation by Innate T Cells

“…Mediators of GvHD include several populations of T cells, such as CD4 + T cells, CD8 + T cells, and CD4/CD8 double-positive populations. These T-cell populations induce GvHD via a perforin-dependent pathway [ 4 ] and secretion of interferons (IFNs) [ 5 ]. Different memory T-cell subsets have varying abilities to mediate GvHD based on their phenotypes.…”