Innate Immune Responses to Aspergillus Mediated by Toll-like Receptors (TLRs) in Patients with Leukemia - 2002

Eric G. Pamer, M.D.

Memorial Sloan Kettering Cancer Center

Funded in September, 2002: $100000 for 2 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Determining How Chemotherapy Limits Immune Defense Against Fatal Fungal Infection

Patients undergoing chemotherapy for leukemia are highly vulnerable to fungal infection, and the mortality rate among patients developing invasive fungal infections is exceedingly high. Developing a better understanding of the immune defense against fungal infection, and how that is compromised in certain patients undergoing chemotherapy, could potentially lead to identifying those at risk and to development of immune-based anti-fungal therapies.

To date, scientists do not know if there are specific defects in immune resistance that mediate the susceptibility to fungal infection in this 20-25% of leukemia patients. The researchers suspect, however, that deficiencies occur in the patients' innate immune system, which ordinarily mounts a rapid but general and short-lived response. In particular, the investigators suggest that alterations occur in Toll-like receptors (TLRs), a family of cell surface receptors that play an active role in the innate resistance to microbial infection.

These TLRs ordinarily recognize molecular patterns associated with pathogens. Similar receptors are present in fruit flies and are essential to their antifungal responses. Increasing evidence suggests that mutations in human TLRs are associated with susceptibility to infections. These variations in TLRs may be associated with differences among individuals in how they respond to fungus. The researchers hypothesize that the immune system's monocytes and dendritic cells [from different individuals] will have different responses to fungus in different individuals based on genetic differences in these TLRs. They will study TLR expression, function and genetic sequence in blood cells isolated from patients prior to chemotherapy. Patient studies are essential to determine if there is an association between TLR malfunction and susceptibility to fungal infection.

ABSTRACT

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Innate Immune Responses to Aspergillus Mediated by Toll-like Receptors (TLRs) in Patients with Leukemia

Toll-like receptors (TLR) are a family of cell surface receptors that play an essential role in innate immune responses to infection. TLRs recognize conserved microbial molecules and initiate direct antimicrobial activity through the activation of NF- B signaling pathway. In addition, TLRs influence the nature of antigen-specific adaptive immune responses by regulating co-stimulatory signals and cytokines. Human TLRs are highly homologous to the toll family of genes in Drosophila. The Toll pathway is critical for antifungal responses in Drosophila. There is little information on the role of TLRs in host defense against fungal pathogens in humans. The possibility that TLRs may be involved in the in vivo recognition of Aspergillus in humans merits study.

The incidence of aspergillosis in patients with acute leukemia is 5-25%, with crude mortality exceeding 85% despite antifungal treatment. Because leukemic patients often have prolonged periods of neutropenia the relative contribution of mononuclear cells to antifungal immunity will be greater. A better understanding of the immune defense against aspergillus has the potential of i) identifying subsets of patients at high risk for developing aspergillosis and ii) leading to novel immune-based antifungal therapies.

We want to test two hypotheses: first, that innate immune responses against aspergillus vary between individuals, perhaps as a result of TLR polymorphisms; and second, that the quality of innate immune responses to Aspergillus correlates with clinical outcome. The objective of the study is to investigate the role of innate recognition of Aspergillus using a combined experimental and clinical approach. First, we will study innate immune activation and signaling in response to Aspergillus antigens in vitro in normal host cells including primary monocytes and dendritic cells obtained from patients with leukemia in remission. Then, we will correlate differences in innate immune activation or signaling with clinical development and outcome of invasive Aspergillosis.

INVESTIGATOR BIOGRAPHIES

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Eric G. Pamer, M.D.

Eric G. Pamer, M.D. obtained his medical degree from Case Western Reserve School of Medicine in 1982, and completed his residency in Internal Medicine at UCSD Medical Center in San Diego. He then obtained training in Infectious Diseases at UCSD Medical Center followed by postdoctoral training in immunology at Scripps Research Institute and at the University of Washington. He spent 8 years on the faculty of Yale School of Medicine and then moved to Memorial Sloan-Kettering Cancer Center in 2000 to head the Infectious Diseases Service. His laboratory focuses on the cellular immune response to infection by intracellular pathogens. More recently they have started to characterize human defense mechanisms against fungal infection, with a specific focus on patients undergoing cancer chemotherapy.