The outcome is in the genes

A simple genetic test could help doctors predict the likelihood that a patient will develop a potentially life-threatening complication after a bone-marrow or stem-cell transplant.

New research conducted by Drs. Ming-Tseh Lin, John Hansen and colleagues in the Clinical Research Division and Taiwan reveals that transplant recipients with a common variant of an immune-system regulator gene are half as likely as other patients to develop clinically severe graft-vs.-host disease. The complication occurs when transplanted cells mount a destructive immune reaction against a patient's body.

The findings, published in the Dec. 4 issue of the New England Journal of Medicine, suggest that inclusion of the genetic test in a patient's standard pre-transplant evaluation could ultimately help doctors determine the optimum timing and course of treatment.

"This clearly supports the hypothesis that genetic variation plays an important role in determining outcome after transplant," Hansen said. "Eventually, I envision that patients will undergo DNA testing for multiple genes that affect transplant outcome. This will give us new dimensions to consider when counseling patients on the appropriateness of the procedure for their condition."

From test to clinical practice

Although Hansen said that his group now plans to validate their findings through larger studies involving patients at multiple cancer centers, authors of an accompanying editorial in the Journal wrote that they believe the data is convincing enough to immediately put the genetic test into clinical practice for transplant candidates.

Patients with leukemia or other life-threatening blood disorders commonly receive blood, or hemotopoietic, stem-cell transplants. The technique involves eliminating or weakening a patient's own blood and immune system with chemotherapy and radiation and replacing it with cells from a tissue-compatible donor. Patients and donors, who may be siblings or unrelated people, must undergo tests to determine the similarity of their tissue-type, or HLA, genes. HLA mismatches can result in graft-vs.-host disease, a condition that causes symptoms ranging from rashes to debilitating or even lethal damage to the digestive system, lungs and other organs.

Even patients who receive transplants from siblings who are exact tissue matches may suffer from graft-vs.-host disease, Hansen said.

"There are clearly other components of the immune system in addition to HLA that influence how individual patients react to the transplant procedure," he said. The extent of tissue injury following high-dose chemotherapy and radiation, and the intensity of inflammatory responses associated with graft-vs.-host disease are controlled by a constellation of immune-regulator genes. "Our work indicates that IL10 is one such gene that contributes significantly to whether this complication occurs following transplants from HLA matched sibling donors."

Interleukin-10

The IL10 gene produces interleukin-10, one of a family of proteins known as cytokines that regulate the body's immune response to infection, injury and transplantation. When released by a transplant recipient's cells, interleukin-10, also known as an anti-inflammatory cytokine, helps prevent transplanted immune cells from mounting a destructive response against the patient's own tissue, even if it is seen as "foreign" by the donor cells. Previous studies have found a correlation between increased production of interleukin-10 by transplant recipients and protection from graft-vs.-host disease.

To evaluate whether DNA differences in the IL10 or other cytokine genes are associated with development of graft-vs.-host disease, Lin and colleagues analyzed 993 patients who received transplants from HLA-matched siblings. The researchers determined the gene sequence of both copies of each patient's IL10 gene as well as the sequences of several other cytokine genes. Researchers also analyzed gene sequences from donors. Gene sequence, or genotype, was then correlated with the occurrence of severe graft-vs.-host disease.

Variations of a gene

The scientists found that patients with two copies of a variant of IL10 called IL10-592A variant (the A/A genotype) were half as likely to develop severe acute graft-vs.-host disease than patients with the C/C genotype. The letters refer to differences in DNA sequence at a particular position within the IL10 gene. Patients with one copy of each variant (A/C genotype) had an intermediate level of risk. In addition, patients with the favorable A/A genotype had a three-year death rate of 13 percent, while those with either the A/C or C/C genotype had three-year death rates of about 25 percent. The researchers do not yet know how the differences in DNA sequence affect the IL10 gene, although they suspect that it leads to increased production of interleukin-10.

Hansen said that eventually doctors will have the power to assemble a genetic profile of potential transplant recipients through DNA sequencing of IL10 and other genes found to affect a patient's response to treatment.

"This will enable us to individualize outcome analysis and prediction," he said. Among the practical applications is more comprehensive counseling for patients considering a transplant.

"When discussing options with a patient, a routine decision that must be made is when is the appropriate time to undertake a transplant," Hansen said. "Currently we consider the patient's diagnosis and stage of disease, age, HLA match and whether the patient has other medical conditions to make that decision. Genetic testing would give us another dimension. A patient with a favorable genotype and a matched donor might want to proceed with a transplant sooner rather than later."

Hansen said that an unfavorable genotype might be an indication for adjusting the dose of administered drugs or it might guide the choice of the type of transplant for an individual patient, for example a mini-transplant versus conventional transplant.

"In addition, the finding that IL10 genotype affects transplant outcome creates a rationale for developing new agents and drug therapy that might enhance the IL-10 effect," he said. "For example, this might provide impetus for seeking new agents we could administer that might modulate a patient's levels of interleukin-10."

Susceptibility and outcome

Hansen said that it is not yet known whether the association of IL10 genotype and graft-vs.-host disease will hold true for transplants between unrelated individuals. A study to address this question is now under way.

The findings also help to explain why the incidence of acute graft-vs.-host disease differs among ethnic groups, Lin said. "Asians have a much lower reported incidence of acute graft-vs.-host disease than Caucasian patients," he said. "The frequency of the A/A genotype among white populations is about 24 percent and is closer to 70 percent in Japanese and Taiwanese populations."

Lin and colleagues at the National Taiwan University have recently found that IL10 genotype also correlates with outcome of hepatitis C virus infection, a disease that is prevalent in Asia.

"I believe that in the future we will see many more examples where genetic variation in immune-response genes affects disease susceptibility and outcome," he said.