GVHD: A Continuing Barrier to the Safety of Allogeneic Transplantation

Abstract

Acute and chronic graft-versus-host disease (GVHD) remain the major clinical complication of allogeneic hematopoietic cell transplantation limiting survival and inducing major morbidity, sometimes for several years posttransplant. In this article, three authors review components of GVHD that underlie these hazards. Dr. Pavan Reddy outlines preclinical, mostly murine data detailing the current understanding of the pathophysiology of acute GVHD. Chronic GVHD, the major ongoing immunologic limitation to transplant success has complexities in its assessment and management and unfortunately, no defined best therapy. Dr. Mukta Arora outlines new strategies for its assessment and describes opportunities for better treatment of this chronic disease. Finally, it is well recognized that acute and chronic GVHD induce their morbidity not just by their end organ toxicity or the side effects of treatment, but the syndrome in itself is immunosuppressive. Chronic GVHD compromises the development of functional defenses against infection and may alter defenses against recurrence of any underlying cancer. Drs. Guimond and Mackall review the impact of GVHD on the immune development post HCT and in doing so, outline ways that therapeutical alternatives might better facilitate immunologic reconstitution. Mouse models have been central to our identification and understanding of the pathophysiologic mechanisms of GVHD, and canine models have been critical to the development of clinically useful strategies for GVHD prophylaxis and treatment [1]. Based largely on these experimental models, the development of acute GVHD can be conceptualized in three sequential steps or phases: (1) activation of the antigen presenting cells (APCs); (2) donor T cell activation, proliferation, differentiation and migration; and (3) target tissue destruction [2]. Phase I: Activation of APCs The first step involves the activation of APCs by the damage caused underlying disease and the HCT conditioning regimen. Damaged host tissues respond by producing “damage associated/danger” signals, including proinflammatory cytokines (e.g., IL-1, IL-6, TNF-α), chemokines, and increased expression of adhesion molecules, MHC antigens and costimulatory molecules on host APCs [1]. Damage to the GI tract from the conditioning is particularly important because it allows for systemic translocation of additional inflammatory stimuli such as microbial products including lipopolysaccaride (LPS) or other pathogen-associated molecular patterns that further enhance the activation of host APCs [3]. The secondary lymphoid tissue in the GI tract is likely the initial site of interaction between activated APCs and donor T cells, but secondary lymphoid tissues are not obligatory for the induction of GVHD [4,5]. These observations have led an important clinical strategy to reduce acute GVHD by reducing the intensity of the conditioning regimen [6]. The concept that enhanced activation of host APCs increases the risk for acute GVHD unifies a number of seemingly disparate clinical associations with that risk, such as advanced stages of malignancy, more intense transplant conditioning regimens and histories of viral infections. Experimental GVHD can also be reduced by manipulating distinct subsets of APCs [7]. Both the host and donor derived hematopoietic APC subsets are relevant for the induction and severity of acute GVHD [8]. However, certain APC subsets have been shown to mitigate GVHD [9], and in addition, non-hematopoietic stem cells, such as mesenchymal stromal cells, acting as APCs can reduce allogeneic T cell responses and ameliorate GVHD, although the mechanism for such inhibition remains unclear [10]. The receptors and signaling pathways that are critical for the activation of APCs and induction of GVHD remain to be determined. Given the redundancy, the critical receptors/pathways might vary depending on the type of BMT, the preparative regimen and the other relevant host/donor conditions. Recent clinical observations suggest that certain polymorphisms that affect APC activation, such as those donor and host NOD2 and donor inflammasome protein-encoding variants in NLRP2 and NLRP3 might be relevant [11,12].