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Graft-versus-host disease

graft-versus-host disease, graft-versus-host disease (gvhd)
Graft-versus-host disease GvHD is a medical complication following the receipt of transplanted tissue from a genetically different person GvHD is commonly associated with stem cell transplant bone marrow transplant, but the term also applies to other forms of tissue graft Immune cells white blood cells in the donated tissue the graft recognize the recipient the host as foreign nonself 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 or treated with an approved pathogen reduction system

Whereas transplant rejection occurs when the host rejects the graft, GvHD occurs when the graft rejects the host The underlying principle alloimmunity is the same, but the details and course may differ


  • 1 Signs and symptoms
    • 11 Types
  • 2 Causes
    • 21 Transfusion-associated GvHD
    • 22 Thymus transplantation
    • 23 Thymoma-associated multiorgan autoimmunity TAMA
  • 3 Prevention
  • 4 Treatment
  • 5 Research
  • 6 See also
  • 7 References
  • 8 Further reading

Signs and symptomsedit

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, eg, the bone marrow and the thymus itself, and the lungs in the form of immune-mediated pneumonitis Biomarkers can be used to identify specific causes of GvHD, such as elafin in the skin1 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 glandscitation needed

Acute GvHD of the GI tract can result in severe intestinal inflammation, sloughing of the mucosal membrane, severe diarrhea, abdominal pain, nausea, and vomiting This is typically diagnosed via intestinal biopsy Liver GvHD is measured by the bilirubin level in acute patients Skin GvHD results in a diffuse red maculopapular rash, sometimes in a lacy patterncitation 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 intercourse2

Acute GvHD is staged as follows: overall grade skin-liver-gut with each organ staged individually from a low of 1 to a high of 4 Patients with grade IV GvHD usually have a poor prognosis If the GvHD is severe and requires intense immunosuppression involving steroids and additional agents to get under control, the patient may develop severe infections as a result of the immunosuppression and may die of infectioncitation needed

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 patients3


In the clinical setting, graft-versus-host-disease is divided into acute and chronic forms, and scored or graded on the basis of the tissue affected and the severity of the reaction


  • The acute or fulminant form of the disease aGvHD is normally observed within the first 100 days post-transplant,6 and is a major challenge to transplants owing to associated morbidity and mortality7
  • The chronic form of graft-versus-host-disease cGvHD normally occurs after 100 days The appearance of moderate to severe cases of cGVHD adversely influences long-term survival8

Currently, there are no reliable molecular markers reflecting the onset or clinical course of aGVHD However, it has been shown that genes responsible for cytokine signaling, inflammatory response, and regulation of cell cycle are differentially expressed in patients with fatal GvHD versus "indolent" GvHD9


GVHD pathology

Billingham Criteria: 3 criteria must be met in order for GvHD to occur2

  • An immuno-competent graft is administered, with viable and functional immune cells
  • The recipient is immunologically different from the donor - histo-incompatible
  • The recipient is immuno-compromised and therefore cannot destroy or inactivate the transplanted cells

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 HLA 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 response10

Antigens most responsible for graft loss are HLA-DR first six months, HLA-B first two years, and HLA-A long-term survival11

While donor T-cells are undesirable as effector cells of graft-versus-host-disease, they are valuable for engraftment by preventing the recipient's residual immune system from rejecting the bone marrow graft host-versus-graft In addition, as bone marrow transplantation is frequently used to treat cancer, mainly leukemias, donor T-cells have proven to have a valuable graft-versus-tumor effect A great deal of current research on allogeneic bone marrow transplantation involves attempts to separate the undesirable graft-vs-host-disease aspects of T-cell physiology from the desirable graft-versus-tumor effectcitation needed

Transfusion-associated GvHDedit

Main article: Transfusion-associated graft versus host disease

This type of GvHD is associated with transfusion of un-irradiated blood to immunocompromised recipients It can also occur in situations in which the blood donor is homozygous and the recipient is heterozygous for an HLA haplotype It is associated with higher mortality 80-90% due to involvement of bone marrow lymphoid tissue, however the clinical manifestations are similar to GVHD resulting from bone marrow transplantation Transfusion-associated GvHD is rare in modern medicine It is almost entirely preventable by controlled irradiation of blood products to inactivate the white blood cells including lymphocytes within12

Thymus transplantationedit

Thymus transplantation may be said to be able to cause a special type of GvHD because the recipient's 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 species13 Autoimmune disease is a frequent complication after human allogeneic thymus transplantation, found in 42% of subjects over 1 year post transplantation14 However, this is partially explained by the fact that the indication itself, that is, complete DiGeorge syndrome, increases the risk of autoimmune disease15

Thymoma-associated multiorgan autoimmunity TAMAedit

A GVHD-like disease called thymoma-associated multiorgan autoimmunity TAMA can occur in patients with thymoma In these patients rather than a donor being a source of pathogenic T cells, the patient's own malignant thymus produces self-directed T cells This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells The end result is a disease virtually indistinguishable from GVHD 16


  • DNA-based tissue typing allows for more precise HLA matching between donors and transplant patients, which has been proven to reduce the incidence and severity of GvHD and to increase long-term survival17
  • The T-cells of umbilical cord blood UCB have an inherent immunological immaturity,18 and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GVHD19 The use of liver-derived hematopoietic stem cells to reconstitute bone marrow has the highest success rate according to recent studiescitation needed
  • Methotrexate, cyclosporin and tacrolimus are common drugs used for GVHD prophylaxiscitation 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,20 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 transplants21


Intravenously administered glucocorticoids, such as prednisone, are the standard of care in acute GvHD7 and chronic GVHD22 The use of these glucocorticoids is designed to suppress the T-cell-mediated immune onslaught on the host tissues; however, in high doses, this immune-suppression raises the risk of infections and cancer relapse Therefore, it is desirable to taper off the post-transplant high-level steroid doses to lower levels, at which point the appearance of mild GVHD may be welcome, especially in HLA mis-matched patients, as it is typically associated with a graft-versus-tumor effectcitation needed


There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention23 Currently, there are no reliable molecular markers reflecting the onset or clinical course of aGVHD However, it has been shown that genes responsible for cytokine signaling, inflammatory response, and regulation of cell cycle are differentially expressed in patinets with fatal GvHD versus „indolent“ GvHD9

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 disease24

In January 2016, Mesoblast released results of a Phase2 clinical trial on 241 children with acute Graft-versus-host disease, that was not responsive to steroids,25 Survival rate was 82% vs 39% of controls for those who showed some improvement after 1 month, and in the long term 72% vs 18% of controls for those that showed little effect after 1 month

See alsoedit

  • Graft-versus-tumor effect
  • Immunosuppression
  • Transplant rejection


  1. ^ Paczesny, S; Levine, JE; Hogan, J; Crawford, J; Braun, TM; 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:101016/jbbmt200812039 
  2. ^ 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 PMID 14677115 doi:101016/jbbmt200308001 
  3. ^ 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 PMID 21119507 doi:101097/TP0b013e3181f9caaa 
  4. ^ Martino R, Romero P, Subirá M, Bellido M, Altés A, Sureda A, Brunet S, Badell I, Cubells J, Sierra J 1999 "Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation International Bone Marrow Transplant Registry" Bone Marrow Transplantation journal 24 3: 283–287 PMID 10455367 doi:101038/sjbmt1701899 
  5. ^ Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME 2005 "National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I Diagnosis and staging working group report" BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 11 12: 945–956 PMID 16338616 doi:101016/jbbmt200509004 
  6. ^ "Improved Management of Graft-Versus-Host Disease" National Marrow Donor Program 
  7. ^ a b Goker, H; Haznedaroglu, IC; Chao, NJ 2001 "Acute graft-vs-host disease Pathobiology and management" Experimental Hematology 29 3: 259–77 PMID 11274753 doi:101016/S0301-472X0000677-9 
  8. ^ Lee, Stephanie J; Vogelsang, Georgia; Flowers, Mary ED 2003 "Chronic graft-versus-host disease" Biology of Blood and Marrow Transplantation 9 4: 215–33 PMID 12720215 doi:101053/bbmt200350026 
  9. ^ a b Verner J, Kabathova J, Tomancova A, Pavlova S, Tichy B, Mraz M, Brychtova Y, Krejci M, Zdrahal Z, Trbusek M, Volejnikova J, Sedlacek P, Doubek M, Mayer J, Pospisilova S "Gene expression profiling of acute graft-vs-host disease after hematopoietic stem cell transplantation" Exp Hematol 40: 899–905e5 PMID 22771791 doi:101016/jexphem201206011 CS1 maint: Multiple names: authors list link
  10. ^ Taylor CJ, Bolton EM, Bradley JA 2011 "Immunological considerations for embryonic and induced pluripotent stem cell banking" Philosophical Transactions of the Royal Society B 366 1575: 2312–2322 PMC 3130422  PMID 21727137 doi:101098/rstb20110030 
  11. ^ Solomon S, Pitossi F, Rao MS 2015 "Banking on iPSC--is it doable and is it worthwhile" STEM CELL REVIEWS 11 1: 1–10 PMC 4333229  PMID 25516409 doi:101007/s12015-014-9574-4 
  12. ^ Moroff, G; Leitman, SF; Luban, NL 1997 "Principles of blood irradiation, dose validation, and quality control" Transfusion 37 10: 1084–92 PMID 9354830 doi:101046/j1537-29951997371098016450x 
  13. ^ 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 doi:104049/jimmunol16631843 
  14. ^ 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 ISBN 978-88-470-0827-4 doi:101007/978-88-470-0828-1_30 
  15. ^ 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 PMC 1885498  PMID 17284531 doi:101182/blood-2006-10-048652 
  16. ^ Wadhera A, Maverakis E, Mitsiades N, Lara PN, Fung MA, Lynch PJ Oct 2007 "Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease" J Am Acad Dermatol 57 4: 683–9 PMID 17433850 doi:101016/jjaad200702027 
  17. ^ 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 PMID 12010826 doi:101182/bloodV99114200 
  18. ^ 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 PMID 12522002 doi:101182/blood-2002-08-2510 
  19. ^ 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 PMID 11407342 doi:101056/NEJM200106143442402 
  20. ^ 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 
  21. ^ 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 PMID 16125590 doi:101016/S0140-67360566996-6 
  22. ^ 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 PMID 11781637 doi:101038/sjbmt1703231 
  23. ^ search of clinicaltrialsgov for Graft-versus-host disease
  24. ^ "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 
  25. ^ "Increased Survival Using MSB Cells In Children With aGVHD" Retrieved 22 Feb 2016 

Further readingedit

  • Ferrara JLM, Deeg HJ, Burakoff SJ Graft-Vs-Host Disease: Immunology, Pathophysiology, and Treatment Marcel Dekker, 1990 ISBN 0-8247-9728-0
  • Polsdorfer, JR Gale Encyclopedia of Medicine: Graft-vs-host disease

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