Graft-versus-host disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]
Overview
The pathophysiology of GvHD is based upon immune activation and inflammation due to donor-derived T cell responses, ultimately resulting in host organ damage.[1] Acute and chronic GvHD has slightly different pathophysiologic mechanisms.[2]
Pathophysiology
The general pathophysiologic processes for GvHD are described as follows:
Acute GvHD
The pathophysiology of acute GvHD involves donor alloreactive T lymphocytes mount an immune attack against recipient tissue.[1] The most common tissues affected are the skin, liver, and gastrointestinal tract.[1] Tissues of cardiac, skeletal muscle, or neurologic origin are typically not affected.[1] The process begins with tissue injury that is produced by the conditioning regimen, before the transplant is even performed.[3] This results in a cytokine storm and inflammatory environment.[3] Donor T cells can recognize an antigen presenting cell (APC) harboring a minor histocompatibility antigen (miHA). APCs are typically dendritic cells, which are professional APCs.[4] miHA are short protein fragments that are derived from intracellular proteins. When donor-derived T cells interact with these Mihas, the immune response is activated.[5] CD4+ T cells recognize Mihas on MHC class II molecules, and CD8+ T cells recognize miHAs on MHC class I molecules. Both CD4+ and CD8+ T cells are known to play an important role in GvHD pathogenesis. Though both host and recipient APCs are present in a patient after a transplant, the host APCs are the key cells that allow for antigen presentation.
Chronic GvHD
One of the hallmark features of chronic GvHD is inflammatory fibrosis.[6] In chronic GvHD, thymic epithelial cells are destroyed by alloreactive T cells.[6] This results in decreased regulatory T cell production. Self-reactive T cells are released from the thymus. Furthermore, B cell homeostasis is disrupted, with resulting increased B cell activation and increased production of pre-germinal center B cells.[6] It has been observed that patients with chronic GvHD have high CD21-negative transitional B cells and low CD27-positive memory B cells.[6]
In 2006, Ferrara and Reddy proposed 3 specific stages in the pathophysiology of GvHD.[7] These stages include:
- Stage I: Host tissue damage from the conditioning regimen. In this stage, proinflammatory cytokines are released.[7]
- Stage II: Activation of donor T cells. In this stage, both host and donor APCs play a role in activating donor lymphocytes. The activated T cells produce a variety of proinflammatory cytokines.[7]
- Stage III: Release of cellular and inflammatory mediators. In this stage, clinical manifestations develop due to cytokine-mediated damage,[7]
T cell subsets
There are multiple T cell subsets involved in the pathophysiology of GvHD, and these have distinct roles in disease onset and progression.
- Th1-type cells: An important component in the immune response is the Th1-type subset and its cytokines TNF-alpha, IL-2, and interferon-gamma. This is typically a pro-inflammatory subset of cells that can exacerbate the disease. The Th1-type response drives acute GvHD.[8]
- Th2-type cells: A Th2-type profile, which includes IL-4, IL-5, IL-6, IL-10, and IL-13, can suppress acute GvHD.[1] [4] There are some exceptions to this observation, as elimination of interferon-gamma can enhance GvHD and loss of IL-4 can reduce GvHD. The Th2-type response is thought to drive chronic GvHD.[8]
- Th17 subset: The Th17 subset has been shown to play a significant role in acute GvHD pathogenesis.[8] Th17 cells are derived from naïve CD4+ T cells after exposure to IL-6 and TGF-beta. These cells coordinate local inflammation via release of cytokines like IL-17 and IL-23.[4] IL-17 normally functions in anti-microbial immunity, but excess IL-17 production can result in autoimmunity and immune activation. This can contribute to worsening GvHD pathophysiology. Current data suggests that we do not have a solid understanding of the role of IL-17 and the Th17 subset in GvHD, but this is currently a focus on research efforts.[4]
- Treg subset: Regulatory T cells (Tregs) normally function in suppression of immune activation, prevention of autoimmunity, and maintenance of immune homeostasis.[6] In GvHD, the Treg repertoire is disrupted, and patients have lower Treg activity in chronic GvHD.[6]
The programmed death-1 (PD-1) pathway is an immune checkpoint pathway that functions to suppress alloreactive T cells.
Current questions about the pathophysiology
We currently do not have a complete understanding about certain aspects of the pathophysiology. These unknown aspects include, but are not limited to:
- The target antigens in the epithelial crypts and bile ducts[9]
- Mechanisms of endothelial damage in the GI tract[9]
- Reason as to why epithelial hyperplasia does not repair damaged mucosa[9]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Al-Chaqmaqchi H, Sadeghi B, Abedi-Valugerdi M, Al-Hashmi S, Fares M, Kuiper R; et al. (2013). "The role of programmed cell death ligand-1 (PD-L1/CD274) in the development of graft versus host disease". PLoS One. 8 (4): e60367. doi:10.1371/journal.pone.0060367. PMC 3617218. PMID 23593203.
- ↑ Schroeder MA, DiPersio JF (2011). "Mouse models of graft-versus-host disease: advances and limitations". Dis Model Mech. 4 (3): 318–33. doi:10.1242/dmm.006668. PMC 3097454. PMID 21558065.
- ↑ 3.0 3.1 Rezvani AR, Storb RF (2012). "Prevention of graft-vs.-host disease". Expert Opin Pharmacother. 13 (12): 1737–50. doi:10.1517/14656566.2012.703652. PMC 3509175. PMID 22770714.
- ↑ 4.0 4.1 4.2 4.3 Yi T, Zhao D, Lin CL, Zhang C, Chen Y, Todorov I; et al. (2008). "Absence of donor [[Th17]] leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease". Blood. 112 (5): 2101–10. doi:10.1182/blood-2007-12-126987. PMC 2518909. PMID 18596226. URL–wikilink conflict (help)
- ↑ Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG (2002). "Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease". J Clin Invest. 109 (10): 1335–44. doi:10.1172/JCI14989. PMC 150980. PMID 12021249.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Socié G, Ritz J (2014). "Current issues in chronic graft-versus-host disease". Blood. 124 (3): 374–84. doi:10.1182/blood-2014-01-514752. PMC 4102710. PMID 24914139.
- ↑ 7.0 7.1 7.2 7.3 Qian L, Wu Z, Shen J (2013). "Advances in the treatment of acute graft-versus-host disease". J Cell Mol Med. 17 (8): 966–75. doi:10.1111/jcmm.12093. PMC 3780546. PMID 23802653.
- ↑ 8.0 8.1 8.2 Villa NY, Rahman MM, McFadden G, Cogle CR (2016). "Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies". Viruses. 8 (3): 85. doi:10.3390/v8030085. PMC 4810275. PMID 27011200.
- ↑ 9.0 9.1 9.2 McDonald GB (2016). "How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver". Blood. 127 (12): 1544–50. doi:10.1182/blood-2015-10-612747. PMC 4807421. PMID 26729898.