New Insights into Graft-Versus-Host Disease and Graft Rejection

Abstract

Allogeneic transplantation of foreign organs or tissues has lifesaving potential, but can lead to serious complications. After solid organ transplantation, immune-mediated rejection mandates the use of prolonged global immunosuppression and limits the life span of transplanted allografts. After bone marrow transplantation, donor-derived immune cells can trigger life-threatening graft-versus-host disease. T cells are central mediators of alloimmune complications and the target of most existing therapeutic interventions. We review recent progress in identifying multiple cell types in addition to T cells and new molecular pathways that regulate pathogenic alloreactivity. Key discoveries include the cellular subsets that function as potential sources of alloantigens, the cross talk of innate lymphoid cells with damaged epithelia and with the recipient microbiome, the impact of the alarmin interleukin-33 on alloreactivity, and the role of Notch ligands expressed by fibroblastic stromal cells in alloimmunity. While refining our understanding of transplantation immunobiology, these findings identify new therapeutic targets and new areas of investigation.

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

“…One of the main steps in aGVHD induction and propagation is the proliferation of donor T cells triggered by DC antigen presentation, the appropriate costimulatory signals, and cytokine environment. This massive expansion begins with T cells entering into and rapidly progressing through the cell cycle (2,3), and antiproliferative regimens, such as methotrexate, cyclophosphamide, or mycophenolate, are routine prophylactic regimens for aGVHD in the clinic (45). Here, we show that inhibition of PRMT5 significantly reduces T cell proliferation with a concomitant decrease in S phase T cells (Figure 7).…”

“…T cell activation via the T cell receptor complex (TCR) involves a complex interaction of signaling networks and subsequent gene transcription pathways that dictate the phenotype of T cell response to antigenic insult. Acute graft-versus-host disease (aGVHD), a T cell-mediated immunological disorder, is a frequent posttransplant complication associated with increased morbidity and mortality in patients who receive allogeneic hematopoietic stem cell transplants (1)(2)(3). The pathogenesis of aGVHD involves the recognition of host minor and major histocompatibility complex antigens by immune-competent, donor-derived T cells that mount an inflammatory reaction, initiating T cell alloantigen recognition followed by expansion, migration, and finally end organ damage due to a combination of proinflammatory cytokine secretion (IFN-γ, TNF-α, IL-17) and direct cytotoxic effects (1)(2)(3).…”

“…Acute graft-versus-host disease (aGVHD), a T cell-mediated immunological disorder, is a frequent posttransplant complication associated with increased morbidity and mortality in patients who receive allogeneic hematopoietic stem cell transplants (1)(2)(3). The pathogenesis of aGVHD involves the recognition of host minor and major histocompatibility complex antigens by immune-competent, donor-derived T cells that mount an inflammatory reaction, initiating T cell alloantigen recognition followed by expansion, migration, and finally end organ damage due to a combination of proinflammatory cytokine secretion (IFN-γ, TNF-α, IL-17) and direct cytotoxic effects (1)(2)(3). Th1 cells producing inflammatory cytokines, such as IL-2, IFN-γ, and TNF-α, are considered the crucial subset of T cells that induce aGVHD (4)(5)(6).…”

Amyloidosis and Renal Disease in Patients with Crohn's Disease

“…Interfering with the trafficking of molecules in Th1 cells and activated macrophages will have the advantage of being potentially beneficial in many of the aforementioned disorders [27]. In fact, the inhibition of integrin αL (CD11a), which together with CD18 forms the LFA-1 complex, has proven to be clinically promising with the use of odulimomab [28] for graft-versus-host-disease and transplant rejection and efalizumab for psoriasis [29]. In addition, natalizumab is very effective in CD and multiple sclerosis.…”

Iterative feature selection method to discover predictive variables and interactions for high-dimensional transplant genomic data

“…The major player in GVHD is the activated T cells that recognize and eliminate alloantigens. These T cell functions are influenced by the complex interactions between regulatory networks, pathways, extracellular environment and the unique conditions induced by transplantation procedures [4]. Thus, it is reasonable to assume that both donor's and recipient's genomes matter in the development of acute GVHD.…”