Graft Versus Host Disease Complete Overview

What is Graft-Versus-Host Disease (GVHD)?

It is a transplant-related syndrome characterized by the engraftment of reactive donor T-cells in an immunosuppressed host, which causes the destruction of host tissues owing to differences in HLA between the donor and host (recipient).

Graft-Versus-Host-Disease is of 2 types

1. Acute Graft-Versus-Host-Disease: It manifests within 3 months of transplant. The most common time of presentation is 2-8 weeks
2. Chronic Graft-Versus-Host-Disease: It manifests > 3 months

Pathogenesis 

Conditioning causes tissue damage. This occurs in the case of the skin and small intestine.

1st Step: Activation of host antigen-presenting cell (APC). When the APC gets activated, IL-12 is released. It can present the antigen to the donor T cells.

2nd Step: Donor T-cell activation: Causes activation of the helper T cell 1 pathway (Th1).

3rd step: Cellular and inflammatory pathway activation: This will cause the release of cellular inflammatory factors. It will also lead to the recruitment of macrophages and CD8 + T cells.They cause apoptosis of the target cells.

Also read: What is Paroxysmal Nocturnal Hemoglobinuria?

Common Organ Systems Involved Initially (Initial Target Organ)

Skin

Earliest target organ involvement. Lead to the development of erythematous maculopapular rash. This rash will become generalized erythroderma (bullae and desquamation of skin). In histopathology, the microscopic examination will show epidermal destruction, including the appendages and features of inflammation in the skin.

GIT

Upper GI involvement will lead to nausea, vomiting, anorexia, abdominal pain, etc. Lower GI involvement will lead to mucosa erosion, flattening of crypts, and inflammation in the intestine. Later, it can progress to bloody diarrhea.

Liver

Biliary radicles and small bile ductules are maximally affected. Hepatocyte injury will increase serum bilirubin levels and AST, ALT, and ALP.

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Prophylaxis of Acute GVHD

All prophylactic regimens increase the risk of infection in the patients due to immunosuppression. In leukemias, an increased risk of recurrence of leukemia is seen. Graft versus leukemic effect gets reduced.

Post-Transplant Pharmacologic Prophylaxis (Most commonly used)

Mainstay: calcineurin inhibitors, e.g., tacrolimus/cyclosporine, either alone or combined with prednisolone/methotrexate/mycophenolate methotrexate/mycophenolate mofetil/anti-T cell antibodies. Cyclophosphamide infusion on days +3 and +5 after transplantation causes donor T-cell depletion. It has been found successful in patients undergoing haploidentical transplantation.

Pre-Transplant Infusion of ATG or Alemtuzumab (ANTI-CD52)

Used in allograft from either an unrelated donor or a partially matched relative.

Other Approaches

Graft T-cell depletion, selective removal of a/b T cells.

Despite prophylaxis, significant acute GVHD develops in approximately 30% of recipients of HSCT from matched siblings and in as many as 60% of HSCT recipients from unrelated donors. The risk for the development of GVHD is increased in:

1. Malignant disease

2. Older donor and recipient age.

3. Patients given an unmanipulated allograft, or GVHD prophylaxis, including only 1 drug.

The most important risk factor for acute GVHD is the presence of disparities for HLA molecules in the donor-recipient pair.

Also read: Hematopoiesis: The Journey Of Blood Cell Production

Management of Acute GVHD

• 1st line therapy is corticosteroids.
  • 40–50% of patients show good responses.
  • 50% will be steroid-resistant acute GVHD.
• 2nd line management in skin-specific GVHD—extracorporeal photopheresis
  • Increases anti-inflammatory effect
  • Causes T-cell apoptosis inhibition.
• 2nd line management in multi-organ GVHD
  • Infusion of mesenchymal stromal cells (MSCs).They cause apoptosis of the target cell.
• Other agents
  • Anti-TNF-ɑ agents like Infliximab and Etanercept
  • Anti-IL-6 agents  
  • Pentostatin

MSCs in Acute GVHD

When MSCs are administered without donor-recipient matching. The target cell can either be target organ tissue or an immune cell. Mechanisms involved:

• Exosome transfer
• Micro-vesicle transfer
• Paracrine secretion
• Organelle transfer via nanotubules
• Apoptotic extracellular vesicles
• Activation of IDO in phagocytes

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Extracorporeal Photopheresis

The whole patient's blood is taken out. Separation of erythrocytes and plasma is done. The leukocyte-enriched plasma remains. 8-MOP (photosensitive agent) is added to this blood.

Ultraviolet light is added. These are combined and reinjected in the same person. It is going to cause apoptosis of skin-specific T lymphocytes.

What is Chronic Graft-Versus-Host-Disease (GVHD)?

Chronic GVHD develops or persists > 3 months after transplantation. It is the most frequent late complication of allogeneic HSCT with an incidence of approximately 25% in pediatric patients.

Chronic GVHD is the major cause of non-relapse mortality and morbidity in long-term HSCT survivors. It resembles an autoimmune disease.

Risk Factors for Chronic GVHD

Unrelated donors were used, even if HLA matched. Use of peripheral blood as a source of stem cells. (PBSCT - Peripheral blood stem cell transplant) Older age of donor and recipient. Underlying malignancy. Female donor and male recipient. Use of TBI (total body irradiation) during preparatory regimens.

Clinical Features of Chronic GVHD

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Management of Chronic GVHD

1st line therapy is corticosteroids. The 2nd line of therapy involves extracorporeal photopheresis, MMF, Rituximab, and Pentostatin. 

In extensive sclerosis, Imatinib mesylate. Treatment duration is 1-3 years

All patients with chronic GVHD need antibiotic prophylaxis—cotrimoxazole (TMP-SMX). The future risk of secondary neoplasm is high, especially if the patient has Fanconi anemia.

Important points 

1. Patients with chronic GVHD involving only the skin and liver have a favorable course.
2. The extensive multi-organ disease may be associated with poor quality of life, recurrent infections associated with prolonged immunosuppressive regimens to control GVHD, and a high mortality rate.
3. Morbidity and mortality related to preceding acute GVHD.
   • Acute GVHD progresses into chronic GVHD. It is usually the most severe form.
   • Acute GVHD gets treated, the latent phase occurs, and the patient develops chronic GVHD in the latent phase. This is the moderately severe form.
   • No acute GVHD. The patient develops DeNovo chronic GVHD. This is the milder form and has a good prognosis.

Also read: Von Willebrand Disease-Classification and Treatment

Hope you found this blog helpful for your NEET SS Pediatrics Hematology Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.

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