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

Eric Pamer, M.D

Memorial Sloan-Kettering Cancer Institute

Funded in June, 2004: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Innate Immune Responses to Determining How Chemotherapy Limits Immune Defense Against Fatal Fungal Infection

The majority of patients with leukemia receive chemotherapy that profoundly suppresses their immune system. One therapy for leukemia, and also patients with lymphoma and myeloma, is allogeneic bone marrow transplantation (BMT). Up to 25% of patients with leukemia or BMT will develop fungal infections. The mortality of fungal infections exceeds 85%, despite antifungal treatment. While all patients with leukemia or allogeneic BMT receive similar immunosuppressive agents, only a small fraction of patients will develop severe infections, suggesting that other, yet to be defined, factors contribute to susceptibility to infection.

Recent studies indicate that certain mutations in genes of the immune system may make individuals more susceptible to infection. We will study whether specific mutations in the Toll-like receptor (TLR) genes alter susceptibility to specific infections. We are going to follow 600 patients that receive chemotherapy for leukemia or BMT recipients at Memorial Sloan Kettering Cancer Center. We will monitor these patients to see who will develop infections after chemotherapy or BMT. We will also identify any mutations that may be present in the TLR genes of the same patients. Finally, we will study whether patients with mutations are more likely to get severe infections compared to individuals without mutations.

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 1) identifying subsets of patients at high risk for developing aspergillosis and 2) leading to novel immune-based antifungal therapies.

INVESTIGATOR BIOGRAPHIES

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Eric Pamer, M.D

Eric G. Pamer, M.D., is Chief, Infectious Diseases Service; Enid A. Haupt Chair in Clinical Investigation; and Head, Laboratory of Antimicrobial Immunity at the Sloan Kettering Institute.

Dr. Pamer 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 before moving 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.

HYPOTHESIS

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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.

Our goal is to identify, within our highly immunocompromised patient population of patients, individuals that may be most vulnerable to infection. This knowledge has the potential of improving the survival of patients with leukemia and bone marrow transplantation.

FINDINGS

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Lay Results:
Infection due to aspergillus occurs in up to 15% of bone marrow transplants and result in death in up to 80% of cases. We hypothesized that disordered immunity and genetic predisposition may each play a role. We found two genetic variants in the innate immune genes TLR1 and TLR6 that are associated with an increased risk of aspergillosis. This knowledge may lead to prevention strategies to prevent a fatal infection.

Scientific Results:
Invasive aspergillosis (IA) after alloeneic bone marrow transplantation (BMT) is associated with up to 80% mortality. Immunosuppression or 3 altered immune response due to genetic variation in the innate immune system may influence susceptibility to aspergillosis. We examined the association between SNPs in TLR1, TLR4 and TLR6 genes and IA in a cohort of BMT donors and recipients treated at Memorial Sloan- Kettering Cancer Center. We found that the presence of TLR1 239G>C (Arg80Thr) or the presence of both TLR1 743A>G (Asn248Ser) and TLR6 745C>T (Ser249Pro) in the recipient is associated with IA.

SELECTED PUBLICATIONS

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Mihu C.N., King E., Yosepovitch O., Taur Y., Jaffe D., Jakubowski A., Pamer E., and Papanicolaou G.A.  Risk factors and attributable mortality of late aspergillosis after T-cell depleted hematopoietic stem cell transplantation. Transpl Infect Dis. 2008 Jun;10(3):162-7.

Kesh S., Mensah N., Peterlongo P., Jaffe D., Hsu K., Van den Brink M., O’Reilly R., Pamer E., Satagopan J., and Papanicolaou G.A. TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation.   Ann N Y Acad Sci. 2005 Dec;1062:95-103.