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| {{Infobox Disease
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| |Name = Graft-versus-host disease
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| |DiseasesDB = 5388
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| |ICD10 = {{ICD10|T|86|0|t|80}}
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| |ICD9 = {{ICD9|996.85}}
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| |MedlinePlus =
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| |eMedicineSubj = med
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| |eMedicineTopic = 926
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| |eMedicine_mult = {{eMedicine2|ped|893}} {{eMedicine2|derm|478}}
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| |MeshID = D006086
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| }}
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| {{SI}}
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| {{CMG}}
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| '''Graft-versus-host disease''' (GVHD) is a common [[complication (medicine)|complication]] of allogeneic [[Hematopoietic stem cell transplantation|bone marrow transplantation]] in which functional immune cells in the transplanted marrow recognize the recipient as "foreign" and mount an immunologic attack.
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| ==Causes==
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| According to the Billingham Criteria, 3 criteria must be met in order for GvHD to occur.
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| 1) Administration of an immunocompetent graft, with viable and functional immune cells.
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| 2) The recipient is immunologically disperate - histoincompatible.
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| 3) The recipient is immunocompromised and therefore cannot destroy or inactivate the transplanted cells.
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| After bone marrow transplantation, [[T cell]]s present in the [[medical grafting|graft]], either as contaminants or intentionally introduced into the host, attack the [[biological tissue|tissues]] of the transplant recipient after perceiving host tissues as antigenically foreign. The T cells produce an excess of [[cytokine]]s, 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 [[Human leukocyte antigen|HLA]]-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors often have genetically different [[protein]]s (called minor histocompatibility antigens) that can be presented by [[Major histocompatibility complex|MHC]] molecules to the recipient's T-cells, which see these antigens as foreign and so mount an immune response.
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| While donor [[T-cell]]s 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 [[leukemia]]s, 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.
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| ==Types==
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| Clinically, graft-versus-host-disease is divided into [[Acute (medical)|acute]] and [[chronic (medicine)|chronic]] forms.
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| * The ''acute'' or ''fulminant'' form of the disease (aGVHD) is normally observed within the first 100 days post-transplant<ref>[http://www.marrow.org/PHYSICIAN/improved_management_gvhd.html Graft versus Host Disease], from the [[National Marrow Donor Program]]</ref>, and is a major challenge to transplants owing to associated morbidity and mortality<ref>{{cite journal |author=Goker H, Haznedaroglu IC, Chao NJ |title=Acute graft-vs-host disease: pathobiology and management |journal=Exp. Hematol. |volume=29 |issue=3 |pages=259–77 |year=2001 |pmid=11274753 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0301-472X(00)00677-9}}</ref>.
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| * 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 <ref>{{cite journal |author=Lee SJ, Vogelsang G, Flowers ME |title=Chronic graft-versus-host disease |journal=Biol. Blood Marrow Transplant. |volume=9 |issue=4 |pages=215–33 |year=2003 |pmid=12720215 |doi=10.1053/bbmt.2003.50026 |url=}}</ref>.
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| 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.
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| ==Clinical manifestation==
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| 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 [[Haematopoiesis|hematopoietic system]]—e.g. the [[bone marrow]] and the [[thymus]]) itself, and the [[lung]]s in the form of idiopathic [[pneumonia|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]].
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| 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.
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| 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.
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| ==Transfusion-associated GVHD==
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| {{main|Transfusion-associated graft versus host disease}}
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| This type of GVHD is associated with [[Blood_transfusion|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 [[Human leukocyte antigen|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.
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| ==Prevention==
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| *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.<ref>{{cite journal |author=Morishima Y, Sasazuki T, Inoko H, ''et al'' |title=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 |journal=Blood |volume=99 |issue=11 |pages=4200–6 |year=2002 |pmid=12010826 |doi= |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12010826}}</ref>.
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| *The T-cells of umbilical cord blood (UCB) have an inherent immunological immaturity<ref>{{cite journal |author=Grewal SS, Barker JN, Davies SM, Wagner JE |title=Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? |journal=Blood |volume=101 |issue=11 |pages=4233–44 |year=2003 |pmid=12522002 |doi=10.1182/blood-2002-08-2510 |url=}}</ref>, and the use of UCB stem cells in unrelated donor transplants has a reduced incidence and severity of GVHD<ref>{{cite journal |author=Laughlin MJ, Barker J, Bambach B, ''et al'' |title=Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors |journal=N. Engl. J. Med. |volume=344 |issue=24 |pages=1815–22 |year=2001 |pmid=11407342 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11407342&promo=ONFLNS19}}</ref>.
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| *[[Methotrexate]], [[cyclosporin A]] and [[tacrolimus]] are common drugs used for GVHD prophylaxis.
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| *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<ref>{{cite journal |author=Hale G, Waldmann H |title=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 |journal=Bone Marrow Transplant. |volume=13 |issue=5 |pages=597–611 |year=1994 |pmid=8054913 |doi= |url=}}</ref>, and general [[immunodeficiency]], resulting in a patient more susceptible to [[virus|viral]], [[bacterium|bacterial]], and [[fungus|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<ref><i>Lancet</i> 2005 Aug 27-Sep 2;366(9487):733-41</ref>.
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| ==Treatment of GVHD==
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| Intravenously administered [[corticosteroids]], such as [[prednisone]], are the standard of care in acute GVHD<ref>{{cite journal |author=Goker H, Haznedaroglu IC, Chao NJ |title=Acute graft-vs-host disease: pathobiology and management |journal=Exp. Hematol. |volume=29 |issue=3 |pages=259–77 |year=2001 |pmid=11274753 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0301-472X(00)00677-9}}</ref> 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.
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| ==Investigational therapies for graft-versus-host disease==
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| There are a large number of clinical trials either ongoing or recently completed in the investigation of graft-versus-host disease treatment and prevention<ref>http://www.clinicaltrial.gov/ct2/results?term=Graft-versus-host+disease search of clinicaltrials.gov for Graft-versus-host disease]</ref>.
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| ==See also==
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| * [[Organ transplant]]
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| **[[Transplant rejection]]
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| * [[Immunology]]
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| ** [[Immunosuppression]]
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| * [[Cancer]]
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| ==References==
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| {{reflist|2}}
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| ==External links==
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| ===Transplantation and immunology===
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| *[http://edumed.unige.ch/apprentissage/immunologie/ Website of Geneva University about transplantation immunology]
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| <br/>{{Organ transplantation}}
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| <!--Categories-->
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| [[Category:Immune system disorders]]
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| [[Category:Transplantation medicine]]
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| <!--Other languages-->
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| [[de:Graft-versus-Host-Reaktion]]
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| [[it:Graft-versus-host disease]]
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| [[ja:移植片対宿主病]]
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| [[fi:Käänteishyljintä]]
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| [[pl:Graft-Versus-Host Disease]]
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| [[pt:Doença enxerto versus hospedeiro]]
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| [[sv:Transplantat-mot-värdsjukdom]]
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| {{WH}}
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| {{WS}}
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