Introduction/Definitions:
Autograph: transplanted tissue from one site on a donor and the recipient. Typical examples are skin replacement in burn repair and the use of a vein to fashion a cronary artery bypass.
Isograph: is tissue from an identical twin.
Allografts: exchanges between genetically different individuals beloning to the same species.
zenograph: tissue exchange between individuals of different species.
Etiology & Symptoms of Graft-versus-host-disease (GVHD):
GVHD (graft-versus-host-disease) occurs when donor derived T cells recognize and react to histo-incompatible recipient antigens leading to a variety of host tissue injuries. GVHD is the major cause of morbidity and mortabiliy after allogeneic BM transplantation, even when siblings are matched at the human luekocyte antigen (HLA) locus. GVHD occurs in both acute and chronic forms, each with different kinetics and distinctive pathology. The skin is the organ the most affected by GVHD and clinical symptoms range form a simple rash to a dramatic epidermolysis. Other affected organs are the gut, the liver, the lung and lymphoid organs. Chronic GVHD occurs less than 100 days after transplantation and affects the same tissues, in addition to the joints and the mucosal surfaces with an incidence of 40-60% in trnasplant recipients surviving more than 100 days.
GVHD should be distinguished with host rejection of graph which occurs when cytotoxic T cells of a host recognize foreign class I MHC markers on the surface of grafted cells, releasing IL-2 as part of a general immune mobilization. Antigen specific helper and cytotoxic T cells then bind to the grafted tissue and secrete lymphokines that bigin the rejection process within 2 weeks of transplantation.
In Graft-Versus-Host Disease (GVHD), passenger lymphocytes, which are donor-derived T cells present in the transplanted tissue or graft, recognize the recipient’s cells as foreign. This recognition is primarily mediated by the interaction of the donor T cell receptors with the Major Histocompatibility Complex (MHC) molecules expressed on the surface of the recipient’s cells.
MHC molecules are highly polymorphic, meaning there’s a wide variety of different MHC alleles within a population. If the donor and recipient are not genetically identical (e.g., in an allogeneic transplant), there will be differences in their MHC molecules, also known as Human Leukocyte Antigens (HLAs).
Donor T cells, still “educated” in the donor’s thymus to recognize peptides presented by their self-MHC, can recognize the recipient’s MHC molecules as foreign, even if they’re not presenting a foreign peptide. This is because the recipient’s MHC molecules, even with similar structures, differ enough from the donor’s self-MHC to trigger an immune response. This recognition can occur in two main pathways: Directly, donor T cells directly recognize intact recipient MHC molecules on the surface of recipient antigen-presenting cells (APCs). This direct recognition can activate a large number of donor T cell clones. Indirectly, recipient APCs capture, process, and present donor MHC peptides to the donor T cells in the context of recipient MHC molecules.
Strategies to Mitigate GVHD:
Regulatory T cells:
–T-reglatory cells Engineered to express CARs:
Chen, (WO/2021/034689) discloses regulatory T cells that are engineered to expressed chimeric antigen receptors (CARS) that target CD83 on antigen-presenting cells to prevent GVHD. The CARS is made up of three domains: an ectodomain, transmembrane domain and an endodomain. The ectodomain includes the CD83 binding region and is responsible for antigen recognition. The antigen recognition domain is typically an scFv. It also optionally contains a signal peptide so that the CAR can be glycosylated and anchored in the cell membrane of the immune effector cell. The transmembrane domain connects the ectodomain to the endodomain and resides within the cell membrane when expressed by a cell. The endodomain transmit an activation signal to the immune effector cell after antigen recognition. For example, the endodomain can contain an intracellular signaling domain and optionally a co-stimulatory signaling region. The signaling domain generaly contains immunoreceptor tyrosine-based activation motifs that activate a signaling cascade when the ITAM is phosphorylated. The “co-stimulatory signaling region” refers to intracellular signaling domains fom costimulatory protein receptors such as CD28 that are able to enhance T cell activaiton by T cell receptors. For example, the CAR can be defined by the formula signal peptide -CD83–hinge domain –transmembrane domain –co-stimulatoyr signaling regions –signaling domain. The T cells which is gnetically modified to express the CAR targeting CD83 is administered to the subject receiving transplanted domor hematopoietic cells or solid organ allografts. CD83 is differentially epxressed on alloreactive T cells. The, the anti-CD83 CAR-T cells will target T cells that cause GVHDand spare graft-versus-leukemia (GVL). Even when donors are fully HLA matched, the minor HLA disparity or the presence of H-Y antigens are sufficient to cause GVHD.