Advances in graft-versus-host disease biology and therapy

Abstract

Allogeneic haematopoietic stem cell transplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence of graft-versus-host disease (GVHD). The past decade has brought impressive advances in our understanding of the role of stimulatory and suppressive elements of the adaptive and innate immune systems from both the donor and the host in GVHD pathogenesis. New insights from basic immunology, preclinical models and clinical studies have led to novel approaches for prevention and treatment. This Review highlights the recent advances in understanding the pathophysiology of GVHD and its treatment, with a focus on manipulations of the immune system that are amenable to clinical application.

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Figure 1. Overall aGVHD cascade

Initiation and maintenance of aGVHD has been conceptualized into 4 phases with feedback loops that self-sustain the process. Although the effect of conditioning phase in aGVHD is not absolutely necessary, in many of the models it activates APCs, via tissue destruction, and improve APC capacity. It also, through release of gut bacteria, PAMPS and chemokines, can activate cellular components of innate immune system that can participate in direct tissue damage and contribute in cytokine storm. Host hematopoietic APCs have perhaps the most important role in initiation of GVHD, but this may depend on the model and the potential role of recipient APCs as well host non-hematopoietic APCs should not be ignored. Following antigen presentation, a strong cytokine response is initiated, promoting greater antigen presentation and recruitment of Teffs, and innate immune cells further contributing to the inflammatory cytokine milieu. Finally, the Teff cells, NK cells, macrophages and pro-inflammatory cytokines (e.g. TNF-α), will result in end organ damage, clinically recognized as aGVHD in the skin, lung, gut and liver. The resulting tissue damage, if not treated, will further escalate the disease, spiraling up the process to higher and more severe stages of GVHD pathology, which is extremely difficult to control.

Figure 2. Critical Factors in development of cGVHD

Pathophysiology of cGVHD. The pathophysiology of cGVHD mostly revolves on the polarization of Th cells to a Th2 cytokine phenotype but there are six hallmarks that are unique to this syndrome. These include damage to the thymus associated with the conditioning regimen and more importantly, occurrence of aGVHD earlier in the post-HSCT course resulting in decreased negative selection of alloreactive CD4+ T cells; Th2 cytokine pattern deviation resulting in release of fibrogenic cytokines such as IL-2, IL-10 and TGFβ; macrophage activation followed by tissue fibroblasts proliferations and activation through release of TGFβ and PDGF from macrophages; lower Treg levels and finally, dysregulation of B-cells leading to emergence of autoreactive B-cells and production of autoreactive antibodies. Its suggested that the latter maybe due to excessive presences of BAFF in the lymphoid microenvironment. All these will results in autoimmune-like systemic syndrome mostly associated with fibroproliferative changes that can occur in almost any organ in body but primarily affecting oral and ocular mucosal surfaces and the skin, lung, kidneys, liver and gut.

Figure 3. Some of the common pathways in T-cells-APC interactions targeted by therapeutic intervention using antibodies or small molecules

The diagram represents naïve T-cell and APC interactions with some of their interactions and the downstream pathways resulting in augmentation of T cell activity and antigen presentation or resulting in anergy and tolerization. Some of the agents that have been used to inhibit these pathways are depicted.

Figure 4. General Overview of Promising Anti-GVHD Therapies

The pathways inside the circle shows the most important pathophysiological pathways in the generation of aGVHD. The boxed outside the circle are some of the promising categories of therapeutic interventions and their most relevant immunological targets in GVHD. Plus signs represent the stimulatory effects and the minus signs represent the inhibitory effects of the therapeutics on a pathway.

Figure 5. Potential targets for cellular immunotherapies in GVHD

Tregs are either formed naturally by thymic differentiation (nTRegs) or are induced in the periphery from naive T-cells. Induced Tregs (iTRegs) can be divided into IL4, IL-10 and TGFβ-producing Th3 cells (CD4+CD25+FOXP3+) and CD25- but CD4+FOXP3+ iTregs that also produce IL-10 and TGFβ. FOXp3- Tr1 cells produce IL-10 and have shown potent suppressive effects on GVHD in the context of total lymphoid irradiation and anti-thymocyte globulin (TLI-ATG) conditioning regimen which also induces the generation of IL4-producing NKT cells. Ex vivo expanded Th2 polarized cell are already in clinical trials for the treatment of aGVHD. NK cells trials are also underway using NK cell infusion or activations of NK cells in vivo to delete alloreactive T cells. Substantial data on suppressive effects of IDO+ T cells, macrophages and DCs, make them prime candidates for future clinical trials. Third party infusion of mesenchymal stem cells (MSCs) for the treatment of GVHD, has created mixed results. Transfer of donor-derived Tregs expanded ex vivo has been more promising. Infusion of ex vivo expanded Myeloid derived stem cells (MDSCs) in pre-clinical models using G-& GM-CSF +/− IL-13 has shown to be feasible with anti-GVHD effect. Injection of pegylated-arginase may have the same benefit and is more practical therapeutically.