Graft-versus-host disease

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Graft-versus-host disease
Classification and external resources
ICD-10 T86.0
ICD-9 279.50
DiseasesDB 5388
MedlinePlus 001309
eMedicine med/926 ped/893 derm/478
MeSH D006086

Graft-versus-host disease (GVHD) is a common complication following an allogeneic tissue transplant. It is commonly associated with stem cell or bone marrow transplant but the term also applies to other forms of tissue graft. Immune cells (white blood cells) in the tissue (the graft) recognize the recipient (the host) as "foreign". The transplanted immune cells then attack the host's body cells. GVHD can also occur after a blood transfusion if the blood products used have not been irradiated.


GVHD pathology

Billingham Criteria, 3 criteria must be met in order for GVHD to occur.[1]

After bone marrow transplantation, T cells present in the graft, either as contaminants or intentionally introduced into the host, attack the tissues of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of cytokines, including TNF-α and interferon-gamma (IFNγ). A wide range of host antigens can initiate graft-versus-host-disease, among them the human leukocyte antigens (HLAs). However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different proteins (called minor histocompatibility antigens) that can be presented by Major histocompatibility complex (MHC) molecules to the donor's T-cells, which see these antigens as foreign and so mount an immune response.[citation needed]



In the clinical setting, graft-versus-host-disease is divided into acute and chronic forms.

  • The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant,[2] and is a major challenge to transplants owing to associated morbidity and mortality.[3]

This distinction is not arbitrary: Acute and chronic graft-versus-host-disease appear to involve different immune cell subsets, different cytokine profiles, somewhat different host targets, and respond differently to treatment.[citation needed] Acute GVHD is likely caused by alloreactive memory T-cells pre-existent in the graft. The mechanisms by which chronic GVHD develops are as yet ill-defined.[citation needed]

Clinical manifestation[edit]

In the classical sense, acute graft-versus-host-disease is characterized by selective damage to the liver, skin (rash), mucosa, and the gastrointestinal tract. Newer research indicates that other graft-versus-host-disease target organs include the immune system (the hematopoietic system, e.g., the bone marrow and the thymus) itself, and the lungs in the form of idiopathic pneumonitis. Biomarkers can be used to identify specific causes of GVHD, such as elafin in the skin.[5] Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also cause damage to the connective tissue and exocrine glands.[citation needed]


Mucosal damage to the vagina can result in severe pain and scarring, and appears in both acute and chronic GVHD. This can result in an inability to have sexual intercourse.[1]


In the oral cavity, chronic graft-versus-host-disease manifests as lichen planus with a higher risk of malignant transformation to oral squamous cell carcinoma in comparison to the classical oral lichen planus. Graft-versus-host-disease-associated oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-hematopoietic stem cell transplantation patients.[6]

Transfusion-associated GVHD[edit]


In thymus transplantation[edit]

Thymus transplantation may be said to be able to cause a special type of GVHD because the recipients thymocytes would use the donor thymus cells as models when going through the negative selection to recognize self-antigens, and could therefore still mistake own structures in the rest of the body for being non-self. This is a rather indirect GVHD because it is not directly cells in the graft itself that causes it but cells in the graft that make the recipient's T cells act like donor T cells. It can be seen as a multiple-organ autoimmunity in xenotransplantation experiments of the thymus between different species.[8] Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over 1 year post transplantation.[9] However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome, increases the risk of autoimmune disease.[10]


  • The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity,[12] and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GVHD.[13] The use of liver-derived hematopoietic stem cells to reconstitute bone marrow has the highest success rate according to recent studies.
  • Methotrexate, ciclosporin and tacrolimus are common drugs used for GVHD prophylaxis.[citation needed]
  • Graft-versus-host-disease can largely be avoided by performing a T-cell-depleted bone marrow transplant. However, these types of transplants come at a cost of diminished graft-versus-tumor effect, greater risk of engraftment failure, or cancer relapse,[14] and general immunodeficiency, resulting in a patient more susceptible to viral, bacterial, and fungal infection. In a multi-center study, disease-free survival at 3 years was not different between T cell-depleted and T cell-replete transplants.[15]

Treatment of GVHD[edit]


Investigational therapies for graft-versus-host disease[edit]


On May 17, 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal, its drug for acute graft-versus host disease in children who have failed to respond to steroid treatment. Prochymal is the first stem cell drug to be approved for a systemic disease.[18]

See also[edit]

Further reading[edit]



  1. ^ a b Spiryda, L; Laufer, MR; Soiffer, RJ; Antin, JA (2003). "Graft-versus-host disease of the vulva and/or vagina: Diagnosis and treatment". Biology of Blood and Marrow Transplantation 9 (12): 760–5. doi:10.1016/j.bbmt.2003.08.001. PMID 14677115. 
  2. ^ "Improved Management of Graft-Versus-Host Disease". National Marrow Donor Program. 
  3. ^ a b Goker, H; Haznedaroglu, IC; Chao, NJ (2001). "Acute graft-vs-host disease Pathobiology and management". Experimental Hematology 29 (3): 259–77. doi:10.1016/S0301-472X(00)00677-9. PMID 11274753. 
  4. ^ Lee, Stephanie J.; Vogelsang, Georgia; Flowers, Mary E.D. (2003). "Chronic graft-versus-host disease". Biology of Blood and Marrow Transplantation 9 (4): 215–33. doi:10.1053/bbmt.2003.50026. PMID 12720215. 
  5. ^ Paczesny, S.; Levine, J.E.; Hogan, J.; Crawford, J.; Braun, T.M.; Wang, H.; Faca, V.; Zhang, Q. et al. (2009). "Elafin is a Biomarker of Graft Versus Host Disease of the Skin". Biology of Blood and Marrow Transplantation 15 (2): 13–4. doi:10.1016/j.bbmt.2008.12.039. PMC 2895410. PMID 20371463. 
  6. ^ Elad, Sharon; Zadik, Yehuda; Zeevi, Itai; Miyazaki, Akihiro; De Figueiredo, Maria A. Z.; Or, Reuven (2010). "Oral Cancer in Patients After Hematopoietic Stem-Cell Transplantation: Long-Term Follow-Up Suggests an Increased Risk for Recurrence". Transplantation 90 (11): 1243–4. doi:10.1097/TP.0b013e3181f9caaa. PMID 21119507. 
  7. ^ Moroff, G; Leitman, SF; Luban, NL (1997). "Principles of blood irradiation, dose validation, and quality control". Transfusion 37 (10): 1084–92. doi:10.1046/j.1537-2995.1997.371098016450.x. PMID 9354830. 
  8. ^ Xia, G; Goebels, J; Rutgeerts, O; Vandeputte, M; Waer, M (2001). "Transplantation tolerance and autoimmunity after xenogeneic thymus transplantation". Journal of immunology 166 (3): 1843–54. PMID 11160231. 
  9. ^ Markert, M. Louise; Devlin, Blythe H.; McCarthy, Elizabeth A.; Chinn, Ivan K.; Hale, Laura P. (2008). "Thymus Transplantation". In Lavini, Corrado; Moran, Cesar A.; Morandi, Uliano et al. Thymus Gland Pathology: Clinical, Diagnostic, and Therapeutic Features. pp. 255–67. doi:10.1007/978-88-470-0828-1_30. ISBN 978-88-470-0827-4. 
  10. ^ Markert, M. L.; Devlin, B. H.; Alexieff, M. J.; Li, J.; McCarthy, E. A.; Gupton, S. E.; Chinn, I. K.; Hale, L. P. et al. (2007). "Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: Outcome of 44 consecutive transplants". Blood 109 (10): 4539–47. doi:10.1182/blood-2006-10-048652. PMC 1885498. PMID 17284531. 
  11. ^ Morishima, Y.; Sasazuki, T; Inoko, H; Juji, T; Akaza, T; Yamamoto, K; Ishikawa, Y; Kato, S et al. (2002). "The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors". Blood 99 (11): 4200–6. doi:10.1182/blood.V99.11.4200. PMID 12010826. 
  12. ^ Grewal, S. S.; Barker, JN; Davies, SM; Wagner, JE (2003). "Unrelated donor hematopoietic cell transplantation: Marrow or umbilical cord blood?". Blood 101 (11): 4233–44. doi:10.1182/blood-2002-08-2510. PMID 12522002. 
  13. ^ Laughlin, Mary J.; Barker, Juliet; Bambach, Barbara; Koc, Omer N.; Rizzieri, David A.; Wagner, John E.; Gerson, Stanton L.; Lazarus, Hillard M. et al. (2001). "Hematopoietic Engraftment and Survival in Adult Recipients of Umbilical-Cord Blood from Unrelated Donors". New England Journal of Medicine 344 (24): 1815–22. doi:10.1056/NEJM200106143442402. PMID 11407342. 
  14. ^ Hale, G; Waldmann, H (1994). "Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases". Bone marrow transplantation 13 (5): 597–611. PMID 8054913. 
  15. ^ Wagner, John E; Thompson, John S; Carter, Shelly L; Kernan, Nancy A; Unrelated Donor Marrow Transplantation Trial (2005). "Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): A multi-centre, randomised phase II–III trial". The Lancet 366 (9487): 733–41. doi:10.1016/S0140-6736(05)66996-6. PMID 16125590. 
  16. ^ Menillo, S A; Goldberg, S L; McKiernan, P; Pecora, A L (2001). "Intraoral psoralen ultraviolet a irradiation (PUVA) treatment of refractory oral chronic graft-versus-host disease following allogeneic stem cell transplantation". Bone Marrow Transplantation 28 (8): 807–8. doi:10.1038/sj.bmt.1703231. PMID 11781637. 
  17. ^ search of for Graft-versus-host disease
  18. ^ "World’s First Stem-Cell Drug Approval Achieved in Canada". The National Law Review. Drinker Biddle & Reath LLP. 2012-06-12. Retrieved 2012-07-01.