J Immunol. Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus

[Giuseppe]

Abstract. Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus.

Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus (1)

John R. Teijaro*, Modesta N. Njau*, David Verhoeven*, Smita Chandran*, Steven G. Nadler, Jeffrey Hasday and Donna L. Farber2,**
Department of Surgery and {dagger} Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; and Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543


The rapid effector functions and tissue heterogeneity of memory T cells facilitate protective immunity, but they can also promote immunopathology in antiviral immunity, autoimmunity, and transplantation.
Modulation of memory T cells is a promising but not yet achieved strategy for inhibiting these deleterious effects. Using an influenza infection model, we demonstrate that memory CD4 T cell-driven secondary responses to influenza challenge result in improved viral clearance yet do not prevent the morbidity associated with viral infection, and they exacerbate cellular recruitment into the lung, compared with primary responses.
Inhibiting CD28 costimulation with the approved immunomodulator CTLA4Ig suppressed primary responses in naive mice infected with influenza, but was remarkably curative for memory CD4 T cell-mediated secondary responses to influenza, with reduced immunopathology and enhanced recovery.
We demonstrate that CTLA4Ig differentially affects lymphoid and nonlymphoid responses to influenza challenge, inhibiting proliferation and egress of lymphoid naive and memory T cells, while leaving lung-resident memory CD4 T cell responses intact.
Our findings reveal the dual nature of memory T cell-mediated secondary responses and suggest costimulation modulation as a novel strategy to optimize antiviral immunity by limiting the memory T cell response to its protective capacities.



The costs of publication of this article were defrayed in part by the payment of page charges.

This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This project was supported by National Institutes of Health Grants AI50632 and AI077029 and by a grant from Bristol-Myers Squibb awarded to D.L.F.

2 Address correspondence and reprint requests to Dr. Donna L. Farber, Department of Surgery, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201. E-mail address: dfarber@smail.umaryland.edu

3 Abbreviations used in this paper: HA, hemagglutinin; BAL, bronchoalveolar lavage; TCID50, tissue culture infectious dose 50%.
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<cite cite="http://www.jimmunol.org/cgi/content/abstract/182/11/6834">Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus -- Teijaro et al. 182 (11): 6834 -- The Journal of Immunology</cite>

[Giuseppe]

Re: J Immunol. Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus

Arthritis drug might prove effective in fighting the flu, study suggests

Arthritis drug might prove effective in fighting the flu, study suggests

University of Maryland researchers see potential new treatment approach in targeting immune response to virus


Researchers at the University of Maryland School of Medicine have found that an approved drug for treating rheumatoid arthritis reduces severe illness and death in mice exposed to the Influenza A virus.


Their findings suggest that tempering the response of the body's immune system to influenza infection may alleviate some of the more severe symptoms and even reduce mortality from this virus.

The scientists report in the June 1 edition of The Journal of Immunology, which is now available online, that mice infected with the Influenza A virus responded favorably to a drug called Abatacept, which is commonly used to treat people with rheumatoid arthritis.

The mice had been given "memory" T-cells, or white blood cells that have been primed to fight the invading virus as the result of previous exposure to Influenza A.

"We found that treating the mice with Abatacept minimized tissue damage caused by the immune response, but still enabled the body to rid itself of the virus. The mice didn't become as sick, recovered much faster and had much less damage to the lungs, compared to mice that weren't given the drug," says Donna L. Farber, Ph.D., a professor of surgery and microbiology and immunology at the University of Maryland School of Medicine and the study's senior author.

"Moreover, treatment with Abatacept significantly improved survival for mice infected with a lethal dose of influenza virus," Dr. Farber says. "The survival rate for the treated mice was 80 percent, compared to 50 percent for the mice that weren't treated."

She explains that the drug does not interrupt the immune system's early, rapid attack in the lungs, which helps to kill the virus, but it prevents "memory" T-cells from overreacting, which produces multiple negative effects.

"It's this overactive immune response that can make you feel sick ? and can also lead to pneumonia," she says.

The study's lead author, John R. Teijaro, a researcher in Dr. Farber's lab, notes that tissue damage caused by this vigorous immune response ? often most prevalent in young, healthy people ? is thought to be the leading cause of death from pandemic strains of flu, such as the avian flu and the 1918 Spanish flu. It is also thought to be true of the early cases of H1N1 "swine" flu.

Dr. Farber says, "We believe that our findings are very significant because they provide a potential new treatment for infection by the influenza virus ? one that would dampen the immune response, yet still preserve its protective effects."

The researchers are now testing Abatacept in mice that have not previously been exposed to the flu virus, trying to determine how well they respond to the drug once they have become very sick. Instead of having "memory" T-cells, these mice have what are known as "na?ve" T-cells, which have never been activated by being exposed to influenza previously. Depending on the results, Dr. Farber hopes to one day bring this promising new immunotherapy to the clinic for the benefit of patients.

E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs, University of Maryland, and dean of the University of Maryland School of Medicine, says, "The results of this study are very promising. Influenza is a significant public health problem, affecting millions around the world each year. We hope that this study ? and Dr. Farber's continuing research ? will pave theway for identifying an effective treatment," Dr. Reece says.

Abatacept, which is manufactured by Bristol-Myers Squibb and marketed under the name Orencia, is already approved by the U.S. Food and Drug Administration for treatment of rheumatoid arthritis. The drug is not approved for treating influenza.

The study, funded by the National Institutes of Health and Bristol-Myers Squibb, is available online at http://www.jimmunol.org/cgi/content/full/182/11/6834.

The Journal of Immunology is a peer-reviewed publication of the American Association of Immunologists.

There are three types of seasonal influenza, A, B and C, and a number of subtypes of Influenza A, including a new strain of the H1N1 virus, also known as the "swine flu," which has recently emerged and caused illness and a number of deaths this year in Mexico, the United States and other countries around the world.

Vaccination is the most effective way to prevent someone from getting the flu or having a serious case of the disease. An antiviral drug, Tamiflu, can help to prevent the flu virus from spreading within the body if it is taken within 48 hours of the first symptoms.

Dr. Farber points out that an immunotherapy with a drug such as Abatacept would be effective against different strains of the virus because the target of the drug would be the immune system, not the virus itself. "We're very excited about the potential of developing a new therapy, which possibly could be given to people even after they are very sick," she says.
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<cite cite="http://www.eurekalert.org/pub_releases/2009-05/uomm-adm052609.php">Arthritis drug might prove effective in fighting the flu, study suggests</cite>