Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

Abstract

Acute graft-versus-host disease (aGVHD) was noted as a complication of allogeneic bone marrow (BM) transplantation in animal models more than six decades ago (1, 2). The initial descriptions of aGVHD differentiated it from the complications of BM aplasia and focused on the severe consequences of GVHD for lower gastrointestinal (GI) tract function, as manifested by weight loss and profound diarrhea. Subsequent studies clearly identified donor T cells as the critical cells required for the induction of aGVHD (3)(4)(5). aGVHD was shown to predominantly involve the skin, liver, and lower GI tract and, later, the upper GI tract (6). In the absence of approaches to prevent aGVHD, this complication occurs in close to 100% of recipients of allogeneic BM/stem cell transplants (allogeneic hematopoietic cell transplantation, allo-HCT), greatly limiting the survival of the first cohort of patients who underwent allo-HCT. Lower GI tract GVHD: clinical findingsDespite the use of prophylaxis to prevent aGVHD, without rigorous T cell depletion this complication occurs in 30%-70% of patients undergoing allo-HCT (7-9). Standard treatment of aGVHD is the administration of systemic corticosteroids and additional immunosuppressive agents, which, as primary therapy, do not substantially improve patient outcomes (10). Thirty to seventyfive percent of patients who develop aGVHD will have a complete response to corticosteroid therapy (11).The outcome for patients with severe aGVHD (grades III-IV) of the lower GI tract is poor, with 25% overall survival (12). Four risk factors (corticosteroid resistance, age under 18 years at time of transplant, GI tract bleeding, and total bilirubin greater than 3 mg/dl) were found on multivariate analysis to be statistically associated with poor survival; no patients with all 4 factors survived, highlighting the critical need to improve survival for these patients. This Review will focus on recent findings regarding the homeostatic mechanisms of the lower GI tract that relate to the pathophysiology of aGVHD involving the distal small intestine and colon. Immune homeostasis in the GI tractThe immune balance of the human small intestine and colon is complex. There are over 100 trillion bacteria that are critical to the function of the GI tract, and individuals are exposed to a huge number of food-borne antigens on a daily basis. Thus, there must exist dynamic and robust mechanisms that mediate immune responses to pathogenic organisms but that prevent immune responses to normal flora and dietary antigens.Antigen-presenting cells in the GI tract. Specialized hematopoietic antigen-presenting cells (APCs) in the GI tract include multiple subpopulations of dendritic cells (DCs) and macrophages ( Figure 1). DCs in the lamina propria (LP) and Peyer's patch sample luminal antigens and migrate to regional lymph nodes (LNs) to activate immune responses (13,14). Macrophages are sessile and are the most abundant innate immune cells in the intestine; they maintain homeostasis by phagocytosing microorganisms and apop...

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability

“…Allogeneic hematopoietic stem cell transplantation (HSCT) is used in the treatment of neoplastic and immune disorders. Graftversus-host disease (GVHD), in which donor-derived T cells target recipient alloantigens to cause tissue pathology, is a common, and frequently severe, complication of HSCT (1). Tissue damage that occurs as a result of pretransplant conditioning is an important factor in GVHD initiation (2,3), and we have demonstrated that this primarily reflects a requirement for intestinal injury and associated barrier loss (4).…”

Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial

“…At the time of this report, 20 of 37 patients are alive and 19 are in complete remission. Six patients received donor lymphocyte infusions owing to disease relapse (5) or incomplete donor engraftment (1). Two of these patients are alive.…”

“…Graft-versus-host disease (GVHD) remains a significant barrier to successful allogeneic hematopoietic cell transplantation (allo-HCT) and is the most common cause of treatment-related mortality in patients with hematologic malignancies, especially when the gastrointestinal (GI) tract is involved [1]. Acute GVHD complicates approximately 30% to 50% of HLA-matched transplantations from related donors and 50% to 70% of transplantations from unrelated donors with standard prophylaxis regimens [2].…”

The Gut Microbiota and Hematopoietic Stem Cell Transplantation: Challenges and Potentials

“…Although antibiotic treatment in stem cell transplant patients is meant to avoid bacterial infections and is essential in many patients, recent studies link these to a higher risk of developing bacterial infections from opportune pathogens and subsequently graft-versus-host disease (GvHD). A significant number of patients receiving allogenic stem cell transplantation develop GvHD, which causes up to 30% mortality in these patients [9]. …”