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GVHD
src: web.stanford.edu

Graft-versus-host disease ( GvHD ) is a medical complication after receiving transplant tissue from genetically different people. GvHD is commonly associated with stem cell transplants as occurs in bone marrow transplantation. GvHD also applies to other forms of transplanted tissue such as solid organ transplants.

White blood cells from the donor immune system that remain in the donated tissue (grafts) recognize the host recipient as foreign (non-self). White blood cells are present in the transplanted tissue and then invade the cells of the receiving body, leading to GvHD. This should not be confused with transplant rejection, which occurs when the transplant recipient immune system rejects the transplanted tissue; GvHD occurs when the white blood cells of the donor immune system reject the recipient. The underlying principle (alloimmunity) is the same, but the details and of course may be different. GvHD may also occur after blood transfusion if the blood product used has not been irradiated or treated with an approved pathogen-reduction system.


Video Graft-versus-host disease



Signs and symptoms

In the classical sense, acute graft-versus-host disease is characterized by selective damage to the liver, skin (rash), mucosa, and gastrointestinal tract. New research suggests that other target organ transplant-versus-host-diseases include the immune system (hematopoietic system, eg, bone marrow and 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 skin. Chronic graft-versus-host disease also attacks the above organs, but over the long-term it can also cause damage to connective tissue and exocrine glands.

Acute GvHD of the gastrointestinal tract can cause severe intestinal inflammation, mucous membrane decay, severe diarrhea, abdominal pain, nausea, and vomiting. These are usually diagnosed through intestinal biopsies. GvHD liver is measured with bilirubin levels in acute patients. Skin GvHD produces a diffuse red maculopapular rash, sometimes in a lacy pattern.

Mucosal damage to the vagina can cause severe pain and scarring, and appears in acute and chronic GvHD. This can cause an inability to have sexual intercourse.

Acute GvHD is staged as follows: overall (skin-liver-intestine) score with each individually staged organ from the lowest 1 to high 4. Patients with fourth-degree GVHD usually have a poor prognosis. If GvHD is severe and requires intense immunosuppression involving steroids and additional agents to be controlled, patients may develop severe infections as a result of immunosuppression and may die from infection.

In the oral cavity, chronic graft-versus-host disease presents as a lichen planus with a higher risk of malignant transformation into oral squamous cell carcinoma compared with classical oral lichen planus. Oral-associated-graft-versus-host-disease-related cancers may have more aggressive behaviors with a worse prognosis, when compared with oral cancer in non-hematopoietic stem cell transplant patients.

Type

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

  • The acute or fulminant form of the disease (aGvHD) is usually observed in the first 100 days after transplantation, and is a major challenge for transplantation due to associated morbidity and mortality.
  • The chronic form of graft-versus-host disease (cGvHD) usually occurs after 100 days. The presence of moderate to severe cGVHD cases may affect long-term survival.

Currently, there are no reliable molecular markers that reflect the onset or clinical course of aGVHD. However, it has been shown that genes responsible for cytokine signaling, inflammatory responses, and cell cycle regulation are differently expressed in patients with fatal GvHD versus indolent GavHD.

Maps Graft-versus-host disease



Cause

Billingham Criteria: 3 criteria must be met for GvHD to occur.

  • An immuno-competent graft is administered, with functioning and functioning immune cells.
  • The recipient is immunologically different from the donor - histo-incompatible.
  • The recipient is immunocompromised and therefore can not destroy or disable transplanted cells.

After bone marrow transplantation, T cells present in the graft, either as contaminants or intentionally inserted into the host, invade the transplant recipient tissue after feeling the host tissue as a foreign antigen. T cells produce excess cytokines, including TNF-? and interferon-gamma (IFN?). A variety of host antigens can initiate graft-versus-host-disease, among them human leukocyte antigens (HLA) antigen. However, graft-versus-host disease can occur even when HLA-identical siblings are donors. HLA-identical siblings or unrelated HLA-identical donors often have genetically different proteins (called minor histocompatibility antigens) that can be presented by Major histocompatibility complex (MHC) molecules to donor T cells, which see this antigen as a foreign body and immune response.

The antigens most responsible for the loss of corruption are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival).

While T cell donors are not desirable as effector cells from graft-versus-host-disease, they are valuable for engraftment by preventing the recipient's immune system from rejecting bone marrow (host-versus-graft). In addition, bone marrow transplants are often used to treat cancer, especially leukemia, T cell donors have been shown to have valuable graft-versus-tumor effects. Much of the current research on allogeneic bone marrow transplantation involves attempting to separate unwanted graft-vs-host-disease aspects of T-cell physiology from the desired graft-versus-tumor effects.

Transfusion-associated GvHD

This type of GvHD is associated with unirradiated blood transfusion to an immunocompromised recipient. This can also occur in situations where homozygous blood donors and heterozygous recipients for the HLA haplotype. This is associated with higher mortality (80-90%) due to involvement of bone marrow lymphoid tissue, but clinical manifestations are similar to GVHD resulting from bone marrow transplantation. Transfusion-related GvHD is rare in modern medicine. This can almost be completely prevented by controlled irradiation of blood products to deactivate white blood cells (including lymphocytes) in them.

Thymus transplant

Thymus transplantation can be said to cause a special type of GvHD because the receiving thymocytes will use donor tymus cells as a model when going through a negative selection to recognize self-antigen, and therefore can still fault its own structure in the rest of the body to become non-self. This is a rather indirect GvHD because it is not the direct cell in the graft itself that causes it but the cells in the graft that make the T cell receiver act like donor T cells. It can be seen as a multi-organ autoimmunity in thymus xenotransplant experiments between different species. Autoimmune disease is a frequent complication after human allogeneic thymus transplant, found in 42% of subjects for more than 1 year post-transplantation. However, this is partly explained by the fact that the indication itself, that is, the complete DiGeorge syndrome, increases the risk of autoimmune disease. Thymoma-associated_multiorgan_autoimmunity_ (TAMA) "> Thymoma-associated multiorgan autoimmunity (TAMA)

A GVHD-like disease called thymoma-associated multiorgan microorganism (TAMA) may occur in patients with thymoma. In these patients rather than donors being the source of pathogen T cells, the patient's own malignant thymus produces self-directed T cells. This is because the malignant thymus is unable to properly educate developing thymocytes to remove self-reactive T cells. The end result is a disease that is almost indistinguishable from GVHD.

Recent advances in the management of graft-versus-host disease ...
src: adc.bmj.com


Mechanism

The pathophysiology of GVHD includes three phases:

  1. APC activation (antigen presenting cells)
  2. Activation, proliferation, differentiation, and effector cell migration
  3. Target network damage

APC activation occurs in the first stage of GvHD. Before hematopoietic stem cell transplantation, radiation or chemotherapy will cause damage and activation of the host tissue, especially the intestinal mucosa. This allows microbial products to enter and stimulate pro-inflammatory cytokines such as IL-1 and TNF-. This proinflammatory cytokine increases the expression of MHC and adhesion molecules in APC, thereby increasing the ability of APC to present antigens. The second phase is characterized by activation of effector cells. Activation of donor T cells further enhances the expression of MHC and adhesion molecules, chemokines and expansion of CD8 and CD4 T-cell and B-cell guests. In the final stages, these effector cells migrate to the target organ and mediate tissue damage, resulting in multiorgan failure.

Alloantigen presentation and graft-versus-host disease: fuel for ...
src: www.bloodjournal.org


Prevention

  • Typing DNA-based networks enable more precise HLA matching between donors and transplant patients, which has been shown to reduce the incidence and severity of GvHD and to improve long-term survival.
  • T-cells from cord blood (UCB) have immunologic immaturity inherent, and use of UCB stem cells in unrelated donor transplants has a decreased incidence and severity of GVHD. The use of hematopoietic stem cells derived from the liver to reshape bone marrow has the highest success rate according to recent research.
  • Methotrexate, cyclosporin and tacrolimus are commonly used drugs for GVHD prophylaxis.
  • Graft-versus-host-disease can be avoided by bone marrow transplantation of T-cell cells. However, these types of transplants result in reduced cost effects of graft-versus-tumor, greater risk of engraftment failure, or recurrence of cancer, and general immune deficiency, resulting in patients more susceptible to viral, bacterial and fungal infections. In a multi-center study, disease-free survival at 3 years did not differ between transplanted T-cells and T cell-replete.

Review Series - January 5, 2017 | Blood Journal
src: www.bloodjournal.org


Treatment

Intravenous glucocorticoids, such as prednisone, are the standard of care in acute GvHD and chronic GVHD. The use of glucocorticoids is designed to suppress T cell-mediated immune defenses in host tissues; however, in high doses, this immune suppression increases the risk of recurrent infections and cancers. Therefore, it is desirable to reduce high-dose post-transplant steroid doses to lower levels, where mild GVHD dosage points are acceptable, especially in patients with HLA-matching, since they are usually associated with tumor-effect graft. Cyclosporine and tacrolimus are calcineurin inhibitors. Both substances are structurally different but have the same mechanism of action. Cyclosporine binds to the cytosolic protein Peptidyl-prolyl cis-trans isomerase A (known as cyclophilin), while tacrolimus binds to the cytosolic protein Peptidyl-prolyl cis-trans isomerase FKBP12. This complex inhibits calcineurin, precludes deposforilasi NFAT transcription factor from activated T-cells and translocation into the nucleus. Standard prophylaxis involves the use of cyclosporine for six months with methotrexate. The cyclosporine level should be maintained above 200 ng/ml. Other substances that have been studied for GvHD treatment include, for example: sirolimus, pentostatin, etanercept, and alemtuzamab.

In August 2017 the US FDA approved ibrutinib to treat chronic GvHD after the failure of one or more other systemic treatments.

Recent advances in the management of graft-versus-host disease ...
src: adc.bmj.com


Clinical research

There is a large number of ongoing or recently completed clinical trials in the investigation of the treatment and prevention of graft-versus-host disease. Currently, there are no reliable molecular markers that reflect the onset or clinical course of aGVHD. However, it has been shown that genes responsible for cytokine signaling, inflammatory responses, and cell cycle regulation are differently expressed in patients with fatal GvHD versus indolent GavHD.

On May 17, 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal, a cure for acute host-graft-versus diseases in children who failed to respond to steroid treatment. Prochymal is the first stem cell drug approved for systemic disease.

In January 2016, Mesoblast released Phase 2 clinical trial results in 241 children with acute Graft-versus-host disease, who were unresponsive to steroids. The experiment was a mesenchymal stem cell therapy known as remestemcel-L or MSC-100-IV. Survival rates were 82% (vs 39% of controls) for those who showed some improvement after 1 month, and in the long run 72% (vs 18% of controls) for those who showed little effect after 1 month.

Acute graft-versus-host disease: from the bench to the bedside ...
src: www.bloodjournal.org


See also

  • The graft-versus-tumor effect
  • Immunosuppression
  • Transplant rejection

Increase in Prevalence of Cancer to Boost Graft vs Host Disease ...
src: mms.businesswire.com


References


How we treat oral chronic graft-versus-host disease | Blood Journal
src: www.bloodjournal.org


Further reading

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

Frontiers | The Role of Pattern-Recognition Receptors in Graft ...
src: www.frontiersin.org


External links

Source of the article : Wikipedia

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