Graft-versus-host disease

Graft-versus-host disease (GVHD) is a condition in which immunologically competent donor T lymphocytes contained in a transplanted graft recognize the recipient's tissues as foreign and mount an immune attack against them.[1][2] It is the mirror image of transplant rejection: in rejection the recipient's immune system attacks the graft, whereas in GVHD the graft's immune cells attack the recipient (the host).[1] GVHD is principally a complication of allogeneic hematopoietic stem cell transplantation (HSCT), where a donor immune system is deliberately transplanted; it is a major cause of morbidity and mortality after HSCT.[1][2] It can also occur, rarely, after transfusion of non-irradiated cellular blood products and after solid-organ transplantation of organs rich in lymphoid tissue.[1][3]

Billingham criteria

The conditions required for GVHD to develop were articulated by Rupert Billingham in 1966 and remain the conceptual foundation of the disease.[1][4] The Billingham criteria state that:[1][4]

• the graft must contain immunologically competent cells (capable of mounting an immune response);
• the recipient must express tissue antigens (transplantation alloantigens) that are foreign to the graft and can therefore stimulate the donor cells; and
• the recipient must be unable to mount an effective immune response to destroy the transplanted cells (for example, because of immunosuppression, immaturity, or tolerance), allowing the donor cells to survive and react.

These conditions explain why GVHD is characteristic of allogeneic HSCT, in which a functioning donor immune system is engrafted into an immunosuppressed, antigenically different recipient, and why it can arise after transfusion in profoundly immunocompromised patients given non-irradiated cellular products.[1][4]

Pathophysiology

GVHD arises from donor T-cell recognition of host alloantigens, principally HLA disparities and minor histocompatibility antigens that differ even between HLA-matched donor and recipient.[1][2] The classical model of acute GVHD describes three phases: (1) tissue damage from the conditioning regimen (chemotherapy/irradiation) and underlying illness releases inflammatory cytokines and damage signals and activates host antigen-presenting cells; (2) donor T cells are activated, proliferate, and differentiate in response to host antigens; and (3) activated effector cells and inflammatory cytokines (a "cytokine storm") cause target-organ injury.[1][2] The degree of HLA mismatch, donor and recipient characteristics, the intensity of the conditioning regimen, and the graft source are major determinants of risk.[1][2]

Acute versus chronic GVHD

GVHD is classically divided into acute and chronic forms, distinguished by clinical features rather than strictly by timing.[1][5]

• Acute GVHD classically presents within the first 100 days after transplantation and characteristically involves three organs: the skin (a maculopapular rash), the gastrointestinal tract (nausea, vomiting, diarrhea, and abdominal pain), and the liver (cholestasis with hyperbilirubinemia).[1][2] Its severity is graded (commonly Glucksberg grades I-IV) according to the extent of skin, gut, and liver involvement, and higher grades carry worse prognosis.[1][2]
• Chronic GVHD typically develops later and is a more protean, multisystem syndrome with features that can resemble autoimmune connective-tissue diseases, including lichenoid or sclerodermatous skin changes, dry eyes and mouth (sicca), oral mucosal disease, bronchiolitis obliterans, and involvement of the liver, joints, and other organs.[1][5] Chronic GVHD is diagnosed and scored by the National Institutes of Health (NIH) consensus criteria, which define diagnostic and distinctive manifestations and a severity score.[5] The older distinction based purely on a 100-day cutoff has been superseded by this clinical/diagnostic framework.[1][5]

Prevention and treatment

Because GVHD is a recognized risk of allogeneic HSCT, prophylaxis is routine.[1][2] Strategies include immunosuppressive prophylaxis (commonly a calcineurin inhibitor such as tacrolimus or ciclosporin combined with methotrexate, with post-transplantation cyclophosphamide increasingly used, particularly for haploidentical and mismatched transplants), careful donor selection to maximize HLA matching, and in some protocols T-cell depletion of the graft.[1][2] T-cell depletion reduces GVHD but can increase relapse and infection, reflecting the linked beneficial graft-versus-tumor (graft-versus-leukemia) effect by which donor T cells also attack residual malignancy.[1][2]

First-line treatment of established acute GVHD is systemic corticosteroids; steroid-refractory disease has a poor prognosis and is treated with additional agents, including the JAK inhibitor ruxolitinib, which is approved for steroid-refractory acute and chronic GVHD.[1][6] Management of chronic GVHD likewise centers on corticosteroids and other immunosuppressants and is guided by organ involvement and severity; specific regimens are individualized clinical decisions.[1][5][6]

Transfusion-associated and solid-organ GVHD

Transfusion-associated GVHD (TA-GVHD) is a rare, usually fatal complication in which viable donor lymphocytes in transfused cellular blood products engraft in a susceptible recipient; it is prevented by irradiation (or pathogen reduction) of cellular blood components for at-risk patients.[1][3] GVHD after solid-organ transplantation is rare and occurs chiefly after transplantation of lymphoid-rich organs such as the intestine and liver, when donor lymphocytes carried in the graft attack the recipient; it carries a high mortality.[1][3] See Intestinal and multivisceral transplantation.

See also

• Transplant rejection
• Transplant immunology
• Immunosuppression in transplantation
• Human leukocyte antigen (HLA) and tissue typing
• Transplant tolerance and mixed chimerism
• Intestinal and multivisceral transplantation

References

• Justiz Vargas AN, Zito PM. Graft Versus Host Disease. StatPearls. NBK538235. https://www.ncbi.nlm.nih.gov/books/NBK538235/
• Zeiser R, Blazar BR. Acute Graft-versus-Host Disease, Biologic Process, Prevention, and Therapy. N Engl J Med. 2017;377(22):2167-2179. PMID:29171820. https://pubmed.ncbi.nlm.nih.gov/29171820/
• Taylor AL, Gibbs P, Bradley JA. Acute graft versus host disease following liver transplantation: the enemy within. Am J Transplant. 2004;4(4):466-474. PMID:15023137. https://pubmed.ncbi.nlm.nih.gov/15023137/ See also: Murali AR, Chandra S, Stewart Z, et al. Graft Versus Host Disease After Liver Transplantation in Adults: A Case Series, Review of Literature, and an Approach to Management. Transplantation. 2016;100(12):2661-2670. PMID:27495762. https://pmc.ncbi.nlm.nih.gov/articles/PMC5118135/
• Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1966;62:21-78. PMID:4875305. https://pubmed.ncbi.nlm.nih.gov/4875305/
• Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2015;21(3):389-401. PMID:25529383. https://pubmed.ncbi.nlm.nih.gov/25529383/
• Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020;382(19):1800-1810. PMID:32320566. https://pubmed.ncbi.nlm.nih.gov/32320566/