Causes and Risk Factors of Graft Versus Host Disease (GVHD)

Causes of GVHD

Graft Versus Host Disease (GVDH) is a serious condition that may arise in a patient following an allogeneic transplant. Between 20% to 80% of people who have a transplant can be at risk of developing the condition. White blood cells, in this case, the T-cells in the donated bone marrow or stem cells, target the host cells for destruction, because they recognize them as foreign.

T-cells are able to recognise which cells are the same as themselves and identify ones that are different and do not have the same genetic markers. The genetic markers on cells which give them their tissue type are the human leukocyte antigens (HLA). HLA are like fingerprints and no two people have the same unless they are identical twins.

In some patients GVHD can begin within the first 100 days after the transplant. This is the acute manifestation of GVHD. Chronic GVHD occurs after 100 days, sometimes even up to a year or more after the transplant and can continue in the patient for a longer period of time. In both acute and chronic presentations of GVHD complications arise in the skin, liver and gastrointestinal tract. However, the chronic manifestation can spread to almost every organ of the body. Occasionally both types of the disease can occur simultaneously. Sometimes a patient develops acute GVHD, which may progress to chronic GVHD at a later stage.

Both types of the disease can be dangerous and may result in death. TH1 type cells are mainly involved in the disease mechanism for acute GVHD and TH2 type cells are predominantly involved in chronic GVHD. Chronic GVHD tends to behave like a syndrome of immune dysregulation triggering immunodeficiency and autoimmunity.

Risks

Unrelated donor transplants

When a host receives a donation from an unrelated donor, the T-cells automatically identify host cells as foreign to their own. This can trigger severe GVHD, because of the different HLA. The tissue type of the donor will be assessed to see if there are any matches. Doctors will choose donors who preferably match in HLA-A, HLA-B, HLA-C and HLA-DRB1.

Mismatched related transplants

When the host and the donor are related, but are not as good a match as identical twins, the donor T-cells can still view the host cells as different and dangerous. For a transplantation to take place, there can be mismatch in HLA-A, HLA-B and HLA-DR, but there is still a much higher risk of GVHD than for matched related donor and host.

Racial mismatch transplants

A donor of a different race is considered high risk, because because it is more difficult to match the HLA. There can also be difficulty finding good tissue type matches for people from minority groups due to the limited population who might be registered.

Female to male mismatch transplants

Males tends to provide higher yields of CD34+ stem cells than females making male donors more preferable as HSCT donors. CD34+ stem cells can change into more than one cell type. Female donors also produce lymphocytes that have memory characteristics. For example, they have a memory of any pregnancies. This can make transplantation more difficult, because of the differences between the sexes. The more pregnancies the donor has had, the more memory of pregnancy is implanted on their cells, which can create a greater risk of GVHD.

Age

The older a donor, the greater this risk of the host developing GVHD. This is not however due to the HLA. The older the patient, the higher the risk of them having other diseases that can cause issues. Physicians will consider each older donor on a case by case basis.

Very insensitive conditioning pre-transplant

High doses of radiotherapy and chemotherapy can increase the risk of GVHD. Before the transplant, the patient may have been subject to these treatments to destroy their own bone marrow cells to make them more receptive to the donor bone marrow cells. This makes the patient weaker as their immune cells have been destroyed. This is also the case for mini-transplant patients although the procedure is less toxic.

Viruses

After a transplant, the patient is at high risk of catching a viral, bacterial or fungal infection as they are lacking the immune cells to fight off disease. To minimise this risk, patients tend to be kept in isolation units.

Cytomegalovirus, related to the herpes virus, can impact HLA expression and increases the risk of acute and/or chronic GVHD. It can also trigger diseases such as hepatitis, pneumonia and gastroenteritis. The chicken pox virus, herpes zoster virus can also cause similar complications.

References

• NHS Christie Hospital on GVHD: http://www.nhs.uk/ipgmedia/Local/The%20Christie%20NHS%20Foundation%20Trust/assets/GVHD-Whatisgraftversushostdisease.pdf
• Progress in Hematology, Effect of HLA mismatch on graft versus host disease: http://download.springer.com/static/pdf/461/art%253A10.1007%252Fs12185-013-1405-x.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs12185-013-1405-x&token2=exp=1460645843~acl=%2Fstatic%2Fpdf%2F461%2Fart%25253A10.1007%25252Fs12185-013-1405-x.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs12185-013-1405-x*~hmac=40e512f038863f35cf7a8ce6d5fef187c386b64dbba8c86155c5d90be1cd4ef7
• Chimerism, Donor parity no longer a barrier for female-to-male hematopoietic stem cell transplantation: http://www.tandfonline.com/doi/full/10.4161/chim.29562
• Blood Journal, How we treat cytomegalovirus in hematopoietic cell transplant recipients:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700312/
• Leukaemia Research on transplants https://www.ebmt.org/Contents/Resources/Library/Patientanddonorpublications/Documents/10.%20LRF_BMT07_4687.pdf
• Blood Journal, Successful Transplantation of HLA-Matched and HLA-Mismatched Umbilical Cord Blood From Unrelated Donors: Analysis of Engraftment and Acute Graft-Versus-Host Disease: http://www.bloodjournal.org/content/bloodjournal/88/3/795.full.pdf?sso-checked=true

Further Reading

• All Graft Versus Host Disease Content
• What is Graft Versus Host Disease (GVHD)?
• Types of Graft Versus Host Disease (GVHD)
• Symptoms and Diagnosis of Graft Versus Host Disease (GVHD)
• Treatment of Graft Versus Host Disease (GVHD)

Written by

Deborah Fields

Deborah holds a B.Sc. degree in Chemistry from the University of Birmingham and a Postgraduate Diploma in Journalism qualification from Cardiff University. She enjoys writing about the latest innovations. Previously she has worked as an editor of scientific patent information, an education journalist and in communications for innovative healthcare, pharmaceutical and technology organisations. She also loves books and has run a book group for several years. Her enjoyment of fiction extends to writing her own stories for pleasure.