Graft-versus-host disease

Graft-versus-host disease is a common complication of allogeneic bone marrow transplantation. 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, and the fierce interplay of these cytokines including TNF alpha and interleukin 1 (IL-1) was first classified as a cytokine storm by Ferrara and co-workers in 1993. A wide range of host antigens can initiate graft-versus-host-disease, among them the HLAs. However, graft-versus-host disease can occur even when HLA-identical siblings are the donors. HLA-identical siblings or HLA-identical unrelated donors (called a minor mismatch as opposed to differences in the HLA antigens, which constitute a major mismatch) often still have genetically different proteins that can be presented on the MHC.

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 cure 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.

Basicaly graft-versus-host-disease is a pathological condition in which cells from the transplanted tissue of a donor initiate an immunologic attack on the cells and tissue of the recipient.

Types

Clinically, graft-versus-host-disease is divided into acute and chronic forms. The acute or fulminant form of the disease is observed within the first 100 days post-transplant, and the chronic form of graft-versus-host-disease is defined as that which occurs after 100 days. This distinction is not arbitrary: acute and chronic graft-versus-host-disease appear to involve different immune cell subsets, different cytokine profiles, and different types of target organ damage.

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 damages the above organs, but also causes changes to the connective tissue (e.g. of the skin and exocrine glands).

GVHD of the GI tract can result in liters of watery diarrhea per day, abdominal pain, nausea, vomiting. This is diagnosed via intestinal biopsy. Liver GVHD is measured by the bilirubin level in acute patients. Skin GVHD results in a diffuse macularpapular rash sometimes in a lacy pattern.

Acute GVHD is staged like the following - overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade 4 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

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.

Prevention

Graft-versus-host-disease can largely be avoided by performing a T-cell depleted bone marrow transplant. These types of transplants result in reduced target organ damage and generally less graft-versus-host-disease, but at a cost of diminished graft-versus-tumor effect, a greater risk of engraftment failure, and general immunodeficiency, resulting in a patient more susceptible to viral, bacterial, and fungal infection. Methotrexate and ciclosporin are common drugs used for GVHD prophylaxis. In a multi-center study (Lancet 2005 Aug 27-Sep 2;366(9487):733-41), disease-free survival at 3 years was not different between T cell depleted and T cell replete transplants.

Bibliography

Graft-vs.-Host-Disease by Ferrara et al. (2nd ed.) published by Marcel Dekker is somewhat out of date, but still a nice bound volume.
Example journals that publish current research on graft-versus-host-disease include The Biology of Blood and Marrow Transplantation, Journal of Clinical Investigation, Journal of Experimental Medicine, Blood, Journal of Immunology, Nature Immunology, Nature Medicine, Immunity, and Transplantation.

External links

National Marrow Donor Program

Graft-versus-Host-Reaktion | 移植片対宿主病

Transplantation medicine | Immunology