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Stem Cell Transplants for Granulomatous Disease Entail Delicate Balancing 

Individuals with the rare inherited disorder called chronic granulomatous disease (CGD), which affects the immune system, are faced with a high and sometimes catastrophic vulnerability to infectious diseases. But delicately managed stem cell transplants from closely matched siblings who are unaffected by this disease to recipients with CGD can enable them to withstand otherwise life-threatening infections and the tissue damage associated with this genetically determined disorder, according to researchers at the National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health (NIH) in Bethesda, Md. 

Despite its narrow immediate applicability, the new stem-cell-based transplant approach being developed at NIAID for treating CGD patients provides valuable insights about conducting cell transplants outside their more-customary realm for treating cancer patients and then orchestrating the suite of complex immune system responses that typically follow such transplant procedures. This CGD management strategy, although promising, entails fine-tuning both recipient and donor immune responses, according to Mitchell Horwitz, Harry Malech, and their collaborators at NIAID, who are testing the new approach on a group of 10 patients and recently reported promising interim results in the New England Journal of Medicine (344:881-888, March 22, 2001). “We will not know whether this treatment is a potential cure until we follow these patients for several more years,” Horwitz says. 

CGD affects little more than 1,000 individuals in the United States, whose death rate is about 5% per year, and perhaps only 25,000 worldwide. Currently, U.S. patients are treated with gamma interferon and daily doses of antibiotics to ward off infections, with Aspergillus fumigatus and Aspergillus nidulans considered perhaps the most problematic. The condition arises when individuals carry mutations affecting one of several subunits of an oxidase enzyme that ordinarily is produced within phagocytes and is essential for certain components of their pathogen-killing repertoire. When available, the properly formed oxidase enables such cells to produce controlled bursts of “activated” oxygen-containing compounds that irreversibly damage various bacterial and fungal pathogens.

Because mutations that cause a defective subunit interfere with production of an effective enzyme, the neutrophils in which this enzyme would be active become crippled in their ordinary capacity to help in killing such pathogens. Even in the absence of those compounds, however, neutrophils still tend to follow parts of their defensive routine. Thus, for example, inappropriate neutrophil activities sometimes yield ungainly, host-damaging accretions, called granulomas, that represent another important clinical manifestation of this life-threatening, inherited disorder.

Transplants of stem cells from tissue-matched siblings whose genes encode a working version of the critical oxidase can restore missing immune system functions in CGD patients and overcome their broad vulnerability to bacterial and fungal pathogens, according to the NIAID research team. However, introducing stem cells, even from such closely matched donors, demands that attending physicians take charge of a careful balancing act—on the one hand, to ensure that functioning components of the recipient's immune system do not reject the donated stem cells and, on the other, to ensure that those introduced cells do not damage the host by means of graft-versus-host disease (GVHD).

Stem cell transplant procedures often begin with radical procedures aimed at destroying the recipient's bone marrow cells and thereby opening the way for cells from the donor to “take” instead of being rejected. However, the NIAID group opted for a less radical and less toxic approach by “conditioning” the recipient's immune system with a medley of immunosuppressive agents instead of out-and-out destroying the bone marrow.

Meanwhile, as part of the counterbalancing strategy for controlling GVHD, the NIAID clinical research team removed T lymphocytes from donor hematopoetic stem cell preparations and then gradually administered some of those donor T cells to the CGD patient at intervals after they had received the T-cell-free stem cell preps. While the donated stem cells replace the missing oxidase and thus restore missing immune system functions in the recipients, the donated T cells help to overcome the tendency of other functioning components (that are unaffected by the oxidase defect) within the recipient's immune system to reject those stem cell grafts.

But, infusing too many donor T cells all at once leads quickly to GVHD. Hence, the NIAID researchers infuse “just enough donor T cells  to have a beneficial effect and clear out the hematopoietic cells of the recipients,” Horwitz says. “In some cases we're successful, and the best control we have is to start with very few T cells  If it gets out of hand and the recipient begins to develop GVHD, then we medicate with immunosuppressive drugs to quell that effect.”

Of the 10 CGD patients who participated in these clinical tests, the 5 children seemed generally to do better. Moreover, their immune systems also proved more likely to reconstitute as mixtures of donor and recipient cell types—in other words, as chimeras, according to Horwitz. “We don't know why the kids were more likely to end up as mixtures, but in this case it's ideal,” he says. “In the future, we're trying to set up such mixtures as a final clinical outcomeand we will take steps to promote that balance.”

Jeffrey L. Fox
Jeffrey L. Fox is the ASM News Current Topics and Features Editor.