Graft-versus-host disease pathophysiology
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Graft-versus-host disease |
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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] The pathophysiology begins with tissue damage from the preparative regimen, then ensues with donor T cell activation, followed by destruction of host tissue in the skin, liver, and/or GI tract. Various T cell subsets play different roles in the pathophysiology of GvHD, and Th1 cells are thought to be major contributors to the inflammation and destruction that underlies the pathophysiology of GvHD.
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.