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{{Infobox medical condition
{{Infobox Disease
| Name          = Selenium deficiency
|Name          = Graft-versus-host disease
| Image          = Se-TableImage.png
|DiseasesDB    = 5388
| Caption        = [[Selenium]]
|ICD10          = {{ICD10|T|86|0|t|80}}
| DiseasesDB    = 11941
|ICD9          = {{ICD9|996.85}}
| ICD10          = {{ICD10|E|59||e|50}}
|MedlinePlus    =  
| ICD9          = {{ICD9|269.3}}
|eMedicineSubj  = med
| ICDO          =
|eMedicineTopic = 926
| OMIM          =
|eMedicine_mult = {{eMedicine2|ped|893}} {{eMedicine2|derm|478}}
| MedlinePlus    =
|MeshID        = D006086
| eMedicineSubj  =
| eMedicineTopic =
| MeshID        =
}}
}}
'''[[Selenium]] deficiency''' is relatively rare in healthy well-nourished individuals. Few cases in humans have been reported.
{{SI}}
{{CMG}}
 
 
 
'''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.  


==Causes==
==Causes==
It can occur in patients with severely compromised [[intestine|intestinal]] function, those undergoing [[total parenteral nutrition]], those who have had gastrointestinal bypass surgery, and also in persons of advanced age (i.e., over 90).<ref>{{cite journal |first1=Giovanni |last1=Ravaglia |first2=Paola |last2=Forti |first3=Fabiola |last3=Maioli |first4=Luciana |last4=Bastagli |first5=Andrea |last5=Facchini |first6=Erminia |last6=Mariani |first7=Lucia |last7=Savarino |first8=Simonetta |last8=Sassi |first9=Domenico |last10=Lenaz |first10=G |last9=Cucinotta |title=Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged ≥90 y |journal=American Journal of Clinical Nutrition |pmid=10648276 |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=10648276 |year=2000 |volume=71 |issue=2 |pages=590–8|display-authors=8 }}</ref>


People dependent on food grown from selenium-deficient soil may be at risk for deficiency.
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.


For some time now, it has been reported in medical literature that a pattern of side-effects possibly associated with [[cholesterol]]-lowering drugs (e.g., [[statins]]) may resemble the pathology of selenium deficiency.<ref>{{cite journal |pmid=15031036 |year=2004 |last1=Moosmann |first1=B |last2=Behl |first2=C |title=Selenoprotein synthesis and side-effects of statins |volume=363 |issue=9412 |pages=892–4 |doi=10.1016/S0140-6736(04)15739-5 |journal=Lancet}}</ref><ref>{{cite journal |pmid=15542379 |year=2004 |last1=Moosmann |first1=B |last2=Behl |first2=C |title=Selenoproteins, cholesterol-lowering drugs, and the consequences: Revisiting of the mevalonate pathway |volume=14 |issue=7 |pages=273–81 |doi=10.1016/j.tcm.2004.08.003 |journal=Trends in Cardiovascular Medicine}}</ref>
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.


==Reference ranges==
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.
In the USA, the [[Dietary Reference Intake]] for adults is 55&nbsp;µg/day. In the UK it is 75&nbsp;µg/day for adult males and 60&nbsp;µg/day for adult females. 55&nbsp;µg/day recommendation is based on full expression of plasma [[glutathione peroxidase]]. [[Selenoprotein P]]<ref name="pmid17508906">{{cite journal |doi=10.1089/ars.2007.1528 |title=From Selenium to Selenoproteins: Synthesis, Identity, and Their Role in Human Health |year=2007 |last1=Papp |first1=Laura Vanda |last2=Lu |first2=Jun |last3=Holmgren |first3=Arne |last4=Khanna |first4=Kum Kum |journal=Antioxidants & Redox Signaling |volume=9 |issue=7 |pages=775–806 |pmid=17508906}}</ref> is a better indicator of selenium nutritional status, and full expression of it would require more than 66&nbsp;µg/day.<ref name="pmid15817859">{{cite journal |pmid=15817859 |year=2005 |last1=Xia |first1=Y |last2=Hill |first2=KE |last3=Byrne |first3=DW |last4=Xu |first4=J |last5=Burk |first5=RF |title=Effectiveness of selenium supplements in a low-selenium area of China |volume=81 |issue=4 |pages=829–34 |journal=The American Journal of Clinical Nutrition}}</ref>


==Signs and symptoms==
==Types==
Selenium deficiency in combination with [[Coxsackievirus]] infection can lead to [[Keshan disease]], which is potentially fatal. Selenium deficiency also contributes (along with [[iodine deficiency]]) to [[Kashin-Beck disease]].<ref name=":0">{{Cite web|url = http://www.atsdr.cdc.gov/toxprofiles/tp92-c3.pdf|title = Toxicological Profile for Selenium|date = September 2003|accessdate = 7 Sep 2015|website = Agency for Toxic Substances and Disease Registry|publisher = U.S. Department of Health and Human Services|last = |first = }}</ref> The primary symptom of Keshan disease is [[myocardium|myocardial]] [[necrosis]], leading to weakening of the heart. [[Kashin-Beck disease]] results in [[atrophy]], degeneration and [[necrosis]] of [[cartilage]] tissue.<ref>{{cite journal |doi=10.1056/NEJM199810153391604 |title=Kashin–Beck Osteoarthropathy in Rural Tibet in Relation to Selenium and Iodine Status |year=1998 |last1=Moreno-Reyes |first1=Rodrigo |last2=Suetens |first2=Carl |last3=Mathieu |first3=Françoise |last4=Begaux |first4=Françoise |last5=Zhu |first5=Dun |last6=Rivera |first6=Maria T. |last7=Boelaert |first7=Marleen |last8=Nève |first8=Jean |last9=Perlmutter |first9=Noémi |last10=Vanderpas |first10=Jean |journal=New England Journal of Medicine |volume=339 |issue=16 |pages=1112–20 |pmid=9770558|display-authors=8 }}</ref> Keshan disease also makes the body more susceptible to illness caused by other nutritional, biochemical, or infectious diseases.
Clinically, graft-versus-host-disease is divided into [[Acute (medical)|acute]] and [[chronic (medicine)|chronic]] forms.  
* 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>.
* 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>.


Selenium is also necessary for the conversion of the thyroid hormone [[thyroxine]] (T4) into its more active counterpart, [[triiodothyronine]],<ref name=":0" /> and as such a deficiency can cause symptoms of [[hypothyroidism]], including extreme [[Fatigue (medicine)|fatigue]], mental slowing, [[goiter]], [[cretinism]], and [[habitual abortion|recurrent miscarriage]].<ref>{{cite web|title = Selenium: Dietary Supplement Fact Sheet|url = http://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/|publisher = National Institutes of Health|accessdate = July 4, 2013}}</ref>
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.


==Epidemiology and prevention==
==Clinical manifestation==
These diseases are most common in certain parts of China where the intake is low<ref name="urlSelenium: Mineral Deficiency and Toxicity: Merck Manual Professional">{{cite web |url=http://www.merck.com/mmpe/sec01/ch005/ch005i.html |title=Selenium: Mineral Deficiency and Toxicity: Merck Manual Professional |work= |accessdate=2008-11-29}}</ref> because the soil is extremely deficient in selenium. Studies in [[Jiangsu Province]] of China have indicated a reduction in the prevalence of these diseases by taking selenium supplements.<ref>{{Cite web|title = Dietary Supplement Fact Sheet: Selenium — Health Professional Fact Sheet|url = http://ods.od.nih.gov/factsheets/selenium.asp|website = ods.od.nih.gov|accessdate = 2015-09-08}}</ref> In Finland, selenium salts are added to chemical fertilizers, as a way to increase selenium in soils.<ref>{{Cite journal|url = http://ajcn.nutrition.org/content/48/2/324.full.pdf|title = Selenium intake and serum selenium in Finland: effects of soil fertilization with selenium|date = 1988|accessdate = 8 September 2015|journal= American Journal of Clinical Nutrition|last = Varo|first = Pertti|last2 = Alfihan|first2 = Georg|last3 = Ekholm|first3 = Paivi|last4 = Aro|first4 = Antti|last5 = Koivistoinen|first5 = Pekka}}</ref>
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]].


==Selenium deficiency in non-human animals==
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.
In some regions (e.g. much of the northeastern and northwestern US and adjacent Canada, and the southeastern US), selenium deficiency in some animal species is common unless supplementation is carried out.<ref name=NRCsheep1985>{{cite book | url = https://books.google.com/books?id=UMb4ZwEACAAJ | title = Nutrient Requirements of Sheep | author1 = Subcommittee On Sheep Nutrition. National Research Council | year = 1985}}</ref>  Selenium deficiency is responsible (either alone or together with vitamin E deficiency) for many of the cases of WMD ("white muscle disease"), evidenced at slaughter or during necropsy by whitish appearance of striated muscle tissue due to bleaching by peroxides and hydroperoxides.<ref>{{cite book |  url = https://books.google.com/books?id=yhgBwjoJ8WoC |  title = Jensen and Swift's diseases of sheep |  isbn = 9780812110999 |  author1 = Kimberling |  first1 = Cleon V |  year = 1988}}</ref> Although this degenerative disease can occur in foals, pigs and other animal species, ruminants are particularly susceptible.<ref>{{cite journal | url = https://books.google.com/books?id=epjiKYkgbIAC | title = The Mineral Nutrition of Livestock | isbn = 9780851991283 | author1 = Underwood | first1 = Eric John | last2 = Suttle | first2 = N. F | year = 1999}}</ref>  In general, absorption of dietary selenium is lower in ruminants than in non-ruminants, and is lower from forages than from grain.<ref name=NRCsr2007>National Research Council, Committee on Nutrient Requirements of Small Ruminants.  2007.  Nutrient requirements of small ruminants.  National Academies Press, Washington.  362 pp.</ref> Sheep are more susceptible than cattle to WMD, and goats are more susceptible than sheep.<ref name=NRCsr2007/> Because of selenium's role in certain peroxidases (converting hydroperoxides to alcohols) and because of the antioxidant role of vitamin E (preventing hydroperoxide formation), a low level of Se can be somewhat (but not wholly) compensated by a high level of vitamin E.  (In the animal, localization of peroxidases and vitamin E differs, partly because of the fat-solubility of vitamin E.)  Some studies have indicated that about 0.12 or 0.23&nbsp;mg Se per kg of dry matter intake may be sufficient for avoiding Se deficiency in sheep in some circumstances.<ref name=NRCsheep1985/>  However, somewhat higher Se intake may be required for avoidance of  WMD where certain legumes are consumed.<ref>Whanger, P. D., P. H. Weswig, J. E. Oldfield, P. R. Cheeke and O. H. Muth.  1972.  Factors influencing selenium and white muscle disease:  forage types, salts, amino acids and dimethyl sulfoxide. Nutr. Rep. Int. 6; 21-37.</ref> The cyanogenic glycosides in some white clover ([[Trifolium repens]]) varieties may influence the Se requirement,<ref name=NRCsr2007/> presumably because of cyanide from the aglycone released by glucosidase activity in the rumen<ref>Coop, I. E. and R. L. Blakely.  1949. The metabolism and toxicity of cyanides and cyanogenic glycosides in sheep. N. Z. J. Sci. Technol. 30: 277-291.</ref> and inactivation of glutathione peroxidases by the effect of absorbed cyanide on the [[glutathione]] moiety.<ref>{{cite journal | pmid = 7426660 | year = 1980 | last1 = Kraus | first1 = RJ | last2 = Prohaska | first2 = JR | last3 = Ganther | first3 = HE | title = Oxidized forms of ovine erythrocyte glutathione peroxidase. Cyanide inhibition of a 4-glutathione:4-selenoenzyme | volume = 615 | issue = 1 | pages = 19–26 | journal = Biochimica et Biophysica Acta | doi=10.1016/0005-2744(80)90004-2}}</ref>


In areas where selenium deficiency in livestock is a concern, selenium (as selenite) may be supplemented in feed. In  some countries, e.g. the US and Canada, such supplementation is regulated. Neonate ruminants at risk of WMD may be administered both Se and vitamin E by injection; some of the WMD myopathies respond only to Se, some only to vitamin E, and some to either.<ref>Kahn, C. M. (ed.) 2005. Merck veterinary manual. 9th Ed. Merck & Co., Inc., Whitehouse Station.</ref>
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==
 
{{main|Transfusion-associated graft versus host disease}}
 
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.
 
==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.<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>.
 
*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>.
 
*[[Methotrexate]], [[cyclosporin A]] 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<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>.
 
==Treatment of GVHD==
 
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.
 
==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<ref>http://www.clinicaltrial.gov/ct2/results?term=Graft-versus-host+disease search of clinicaltrials.gov for Graft-versus-host disease]</ref>.
 
==See also==
* [[Organ transplant]]
**[[Transplant rejection]]
* [[Immunology]]
** [[Immunosuppression]]
* [[Cancer]]


==References==
==References==
{{reflist|2}}
{{reflist|2}}


{{Nutritional pathology}}
<!--Categories-->
 
[[Category:Immune system disorders]]
[[Category:Mineral deficiencies]]
[[Category:Transplantation medicine]]
[[Category:Selenium]]

Revision as of 15:36, 3 June 2016

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

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 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]
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