Graft-versus-host disease (GVHD) is an immune reaction resulting from the donor T cells’ (lymphocytes’) lack of recognition of the recipient’s human leukocyte antigens (HLAs). So, the donor T cells see the patient as foreign, causing an immune reaction. GVHD is the most common complication after allogeneic stem cell transplantation (SCT). It occurs in 30% to 70% of all adult patients receiving allogeneic SCT. In children, the incidence is lower at approximately 30% to 45%.
Why Learn About the Pathophysiology of Acute GVHD?
During the past few years, much has been learned about the pathophysiology of acute GVHD. Please note this process is not the same process that occurs in chronic GVHD. This understanding of the pathogenesis helps to:
- Affect strategies to balance GVHD with the immunologic graft-versus-tumor (GVT) effect. GVT occurs when the donor T cells in the transplanted immune system eliminate residual tumor cells. A mild case of GVHD can be good because this immune response to the patient’s tumor cells (GVT) helps prevent relapse.
- Improve the care team’s comprehension of various prevention and treatment strategies. Better understanding of the multiple pathways can lead to potential drug targets. Oncology nurses can better appreciate and educate about a comprehensive drug approach to GVHD management.
- Provide insight into the critical role of biomarkers to help detect GVHD before the start of symptoms. Biomarkers are measurable substances (e.g., cytokines, T-cell surface markers, or proteins) that can help with GVHD management.
What Are the 3 Phases of Acute GVHD?
The current model of the pathogenesis of acute GVHD involves 3 overlapping phases, according to Schmit-Pokorny and Eisenberg:
Phase 1. Host Tissue Damage and Antigen Presentation. The first phase starts before the infusion of the donor stem cells. The conditioning regimen (chemotherapy with or without total body irradiation) causes tissue damage as it kills both healthy cells and tumor cells. The tissue damage triggers the release of pro-inflammatory cytokines (e.g., IL-1, TNF-α, TGF-β, and others). These actions imbalance the gut microbiome. The cytokines activate the host antigen-presenting cells (APCs), which are mainly in the skin, liver, gut, immune system, lungs, and other organs. The T cells from the donor see the APCs in the host (patient) as foreign and start to attack by triggering an inflammatory cascade.
Phase 2. Donor T Cell Activation. The donor T cells escalate their response by increasing the number and production of various T cells (CD4 and CD8). In addition, costimulatory signals direct helper T cells (Th1) to produce IL-2, IL-12, and interferon-γ to attract cytotoxic T-lymphocytes and natural killer cells. As a result, the cytokine release in phases 1 and 2 causes massive inflammation.
Phase 3. Target Tissue Destruction. In the final phase, the activated T lymphocytes cause direct or indirect tissue destruction. TNF-α can induce tissue necrosis that directly or indirectly triggers apoptosis (or cell death). The major tissue damage is to the skin, liver, and gut—these are called the “target organs” of acute GVHD.
From Malad et al. Leukemia. 2020;34(5):1229-1240.
The process continues as more tissue injury releases more cytokines to promote GVHD. The way to stop the cycle is immunosuppression.
What Are the Key Takeaways from the Pathophysiology of Acute GVHD?
The pathogenesis of acute GVHD is quite complex, with several key discussion points.
- First, combining GVHD risk reduction strategies is critical to preventing or reducing risk: carefully selecting the donor, manipulating the graft for some patients, and administering various pharmaceutical strategies. Both immunosuppressant and immunomodulation agents help deplete T cells to reduce T-cell reactions. Selection and combination of agents remain under exploration for different donor sources.
- Second, damage to the gut and gut GVHD causes a loss of microbial diversity and overgrowth of intestinal pathogens. This gut microbiome disruption allows for more infections, such as enterococcus gram-positive bacteria. These microbes cause more harm and worse GVHD. Prebiotics/probiotics, antibiotic stewardship in neutropenic patients, and fecal microbial transplant are just 3 strategies to improve microbial diversity.
- Finally, biomarkers may help with GVHD risk, diagnosis, or prognosis. Currently, they have more of a role in managing chronic GVHD, but their role in acute GVHD is evolving quickly.
Each transplant center has specific protocols or clinical pathways to help team members manage patients with GVHD and provide supportive care. With a basic understanding of the pathogenesis of acute GVHD and the science behind clinical decisions, nurses can better educate and support their patients and caregivers throughout their transplant journey.
- Schmit-Pokorny K, Eisenberg S, editors. Hematopoietic Stem Cell Transplantation: A Manual for Nursing Practice, 3rd Edition. Oncology Nursing Society; 2020.
- Malard F, Huang XJ, Sim JPY. Treatment and unmet needs in steroid-refractory acute graft-versus-host disease. Leukemia. 2020;34(5):1229-1240. doi:10.1038/s41375-020-0804-2
- Le Bastard Q, Chevallier P, Montassier E. Gut microbiome in allogeneic hematopoietic stem cell transplantation and specific changes associated with acute graft vs host disease. World J Gastroenterol. 2021 Dec 7;27(45):7792-7800. doi:10.3748/wjg.v27.i45.7792.
- Robin M, Porcher R, Michonneau D, Taurines L, Sicre de Fontbrune F, Xhaard A, Oriano B, Sutra Del Galy A, Peffault de Latour R, Socié G, Schlageter MH. Prospective external validation of biomarkers to predict acute graft-versus host disease severity. Blood Adv. 2022 Jun 6:bloodadvances.2022007477. doi:10.1182/bloodadvances.2022007477. Epub ahead of print.