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Graft-versus-host disease

Graft-versus-host disease
Classification and external resources
ICD-10 T86.0
ICD-9-CM 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 or treated with an approved pathogen reduction system.

Contents

  • Signs and symptoms 1
    • Types 1.1
  • Causes 2
    • Transfusion-associated GvHD 2.1
    • Thymus transplantation 2.2
  • Prevention 3
  • Treatment 4
  • Research 5
  • See also 6
  • References 7
  • Further reading 8

Signs and symptoms

In the classical sense, acute graft-versus-host-disease is characterized by selective damage to the connective tissue and exocrine glands.

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 erythematous maculopapular rash, sometimes in a lacy pattern.

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.[2]

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 infection.

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.[3]

Types

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,[4] and is a major challenge to transplants owing to associated morbidity and mortality.[5]
  • 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 survival.[6]

Causes

GVHD pathology

Billingham Criteria: 3 criteria must be met in order for GvHD to occur.[2]

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 response.

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 effect.

Transfusion-associated GvHD

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) within[7]

Thymus transplantation

  • 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

Further reading

  1. ^ 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.  
  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.  
  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.  
  4. ^ "Improved Management of Graft-Versus-Host Disease".  
  5. ^ a b Goker, H; Haznedaroglu, IC; Chao, NJ (2001). "Acute graft-vs-host disease Pathobiology and management". Experimental Hematology 29 (3): 259–77.  
  6. ^ 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.  
  7. ^ Moroff, G; Leitman, SF; Luban, NL (1997). "Principles of blood irradiation, dose validation, and quality control". Transfusion 37 (10): 1084–92.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  17. ^ search of clinicaltrials.gov 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. 

References

See also

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]

There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention.[17]

Research

Intravenously administered glucocorticoids, such as prednisone, are the standard of care in acute GvHD[5] and chronic GVHD.[16] 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 effect.

Treatment

  • 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 survival.[11]
  • 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.
  • 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]

Prevention

[10]

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