Graft-versus-host disease

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Graft-versus-host disease
ICD-10 T86.0
ICD-9 996.85
DiseasesDB 5388
eMedicine med/926  ped/893 derm/478
MeSH D006086

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack.

Causes

According to the Billingham Criteria, 3 criteria must be met in order for GvHD to occur. 1) Administration of an immunocompetent graft, with viable and functional immune cells. 2) The recipient is immunologically disperate - histoincompatible. 3) The recipient is immunocompromised 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 alpha and interferon-gamma (IFNg). 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 MHC molecules to the recipient'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). Additionally, 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.

Types

Clinically, 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[1], and is a major challenge to transplants owing to associated morbidity and mortality[2].
  • 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 [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.

Clinical manifestation

Classically, acute graft-versus-host-disease is characterized by selective damage to the liver, skin and 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. Chronic graft-versus-host-disease also attacks the above organs, but over its long-term course can also causes 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 maculopapular rash, sometimes in a lacy pattern.

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.

Transfusion-associated GVHD

This type of GVHD is associated with transfusion of un-irradiated blood to immunocompromised recipients. It can also occur in situations where 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.

Prevention

  • 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.[4].
  • The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity[5], and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GVHD[6].
  • 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[7], 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[8].

Treatment of GVHD

Intravenously administered corticosteroids, such as prednisone, are the standard of care in acute GVHD[9] and chronic GVHD. The use of these corticosteroids 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.

Investigational therapies for graft-versus-host disease

There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention[10].

See also

References

  1. Graft versus Host Disease, from the National Marrow Donor Program
  2. Goker H, Haznedaroglu IC, Chao NJ (2001). "Acute graft-vs-host disease: pathobiology and management". Exp. Hematol. 29 (3): 259–77. PMID 11274753.
  3. Lee SJ, Vogelsang G, Flowers ME (2003). "Chronic graft-versus-host disease". Biol. Blood Marrow Transplant. 9 (4): 215–33. doi:10.1053/bbmt.2003.50026. PMID 12720215.
  4. Morishima Y, Sasazuki T, Inoko H, 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.
  5. Grewal SS, 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.
  6. Laughlin MJ, Barker J, Bambach B, et al (2001). "Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors". N. Engl. J. Med. 344 (24): 1815–22. PMID 11407342.
  7. 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 Transplant. 13 (5): 597–611. PMID 8054913.
  8. Lancet 2005 Aug 27-Sep 2;366(9487):733-41
  9. Goker H, Haznedaroglu IC, Chao NJ (2001). "Acute graft-vs-host disease: pathobiology and management". Exp. Hematol. 29 (3): 259–77. PMID 11274753.
  10. http://www.clinicaltrial.gov/ct2/results?term=Graft-versus-host+disease search of clinicaltrials.gov for Graft-versus-host disease]

External links

Transplantation and immunology


de:Graft-versus-Host-Reaktion

it:Graft-versus-host diseasefi:Käänteishyljintäsv:Transplantat-mot-värdsjukdom



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