Cytokine disruption study sheds light on increased risk for non-Hodgkin’s lymphoma in AIDS patients

ABSTRACT: Researchers hunt for the biological mechanisms that link HIV infection with lymphoma.

HIV's disruption of immune system function may cause the immune system cells themselves to become cancerous, NCI researchers have concluded. If so, this might explain why patients with AIDS are 100 times more likely to be diagnosed with non-Hodgkin's lymphoma than the general population.

"The fact that AIDS causes cytokine disruption-that it's a condition in which cytokine signaling is recognized to be abnormal-and is also associated with high risk of NHL, made our hypothesis appealing," said lead investigator Charles Rabkin, MD.

Although previous studies have noted elevations in proinflammatory cytokines in AIDS-related NHL patients, this study is the first to analyze a wide range of cytokines. The researchers measured levels of 30 different cytokines in blood and serum samples from their subjects. Blood and serum were obtained from 66 HIV-positive cases, up to two years prior to a diagnosis of NHL. Each of these cases was compared with three HIV-positive lymphoma-free controls matched for age, race, sex, and CD4 count at diagnosis.

"We saw a generalized pattern of increases in cytokine levels that could not be appreciated in individual studies of single cytokines." - CHARLES RABKIN, MD

Dr. Rabkin's group found that blood levels of nine different T-helper and proinflammatory cytokines were significantly higher in HIV-infected patients who later developed NHL than in similar controls.

The researchers' analysis indicated that granulocyte-monocyte–stimulating factor (GM-CSF) and interleukins (IL)-12p70 and IL-15 were most predictive of later development of NHL in the HIV-infected patients (AACR 2010 abstract 5746). "We saw a generalized pattern of increases in cytokine levels that could not be appreciated in individual studies of single cytokines," said Dr. Rabkin, senior investigator at the NCI infections and immunoepidemiology branch.

Does Epstein-Barr virus inform NHL?

Epstein-Barr virus has been suggested as a potential mechanism for the development of NHL in AIDS patients. Dr. Rabkin's group measured Epstein-Barr levels in the blood of their subjects, but found no associations with lymphoma risk.

However, half the samples they collected were not informative because heparin use may have interfered with the PCR reaction used to look for the virus. "There was a trend for Epstein-Barr virus in the blood to be associated with subsequent lymphoma, although it wasn't statistically significant. So we don't think that this is the end of the hypothesis linking the virus to increased risk of NHL in AIDS patients," Dr. Rabkin said.

Dr. Rabkin noted that since cytokines work together to generate their effects, excessive cytokine signaling may contribute to lymphoma risk in AIDS. Their study implies that disruption of immune system function by HIV causes the immune system cells themselves to become cancerous. If the findings are confirmed, future research needs to determine whether modifying cytokine levels could prevent lymphoma in HIV-infected individuals, Dr. Rabkin said.

He noted that one of the strengths of the study was the close match investigators were able to obtain between HIV patients who developed NHL and those who did not. A newly improved measurement technique, using fluorescent beads, also made it possible to use smaller volumes of blood to analyze a wide range of cytokine levels more accurately, he added.

Dr. Rabkin acknowledged that the study sample was small, and the cases do not cover the entire spectrum of AIDS. "I think it's a study that warrants attention and replication, but it's not definitive," he said.

The next step for the researchers is to study cytokine levels in a larger number of patients who develop AIDS-related NHL and match them to similar HIV patients who have not been diagnosed with the cancer. They also will look to see if cytokine signaling could be disrupted early on in the HIV infection process. They plan to revisit earlier blood and serum samples from the same patients to identify levels of cytokines.

"We'd like to see if the disruption in cytokine levels happens only close to the time of lymphoma or early on in the course of HIV infection," Dr. Rabkin said.

VANTAGE POINT

AMRITA KRISHNAN, MD Deciphering the pathogenesis of NHL in HIV-positive patients

This study is important because it explains the pathogenesis of non-Hodgkin's lymphoma in AIDS patients and why HIV-infected patients remain at increased risk for the cancer even in the age of antiretroviral therapy, said Dr. Krishnan, a hematologic oncologist. She is also director of the multiple myeloma program at the City of Hope Comprehensive Cancer Center in Duarte, Calif.

"It explains why antiretroviral therapy has not changed the incidence of NHL in AIDS patients and why [NHL] continues to be a problem," said Dr. Krishnan, whose research at City of Hope concentrates on outcomes for patients with HIV-related lymphomas who receive stem cell transplants.

Dr. Krishnan noted that the most important strength of the study was that the investigators analyzed levels of a whole spectrum of different cytokines that might play a role in the development of NHL. "But the study still looked at only a small number of patients, when there are a lot of patients with HIV and lymphoma with different characteristics," she said. Dr. Krishnan also noted that studying samples taken two years before the NHL diagnosis leaves a fairly long time in which a number of clinical factors could affect the patients' risk for development of NHL.

She also pointed out that the samples were taken at only one time point. "I would have liked to see them measure cytokine levels at several different time points. And if you saw persistent elevation, then it would be a more interesting study, and I would believe it more," she said.

Areas for future research should include the possibility that treatment for HIV or AIDS can cause abnormal cytokine levels to decrease. It would be informative to analyze cytokine levels in patients who did not respond to treatment, she said.

"It might be cost-prohibitive, but it would be interesting to follow patients over the course of their HIV infection and correlate levels of cytokines to risk of developing malignancy," she said.