Cytheris study: rhIL-7 treatment restores T cell trafficking and improves survival in animal model of sepsis

Mar 16 2010

Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced publication of data from a preclinical study in a clinically relevant animal model of sepsis showing that recombinant human Interleukin-7 (rhIL-7) treatment not only restores T cell trafficking and function, but also translates into improved survival. Sepsis, a highly lethal disorder which occurs during severe overwhelming infection, is the most common cause of death in most intensive care units in developed countries, annually striking an estimated 750,000 people in the United States alone, resulting in the death of more than 220,000 people per year.

“IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis”

The paper entitled “IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis” is prepublished online in The Journal of Immunology, the journal of The American Association of Immunologists (Jacqueline Unsinger, Margaret McGlynn, Kevin R. Kasten, Andrew S. Hoekzema, Eizo Watanabe, Jared T. Muenzer, Jacquelyn S. McDonough, Johannes Tschoep, Thomas A. Ferguson, Jonathan E. McDunn, Michel Morre, David A. Hildeman, Charles C. Caldwell, and Richard S. Hotchkiss, March 3, 2010; doi:10.4049/jimmunol.0903151).

The study strongly supports the belief that rather than being an uncontrolled inflammatory response, sepsis is the result of extensive apoptosis-induced depletion of immune effector cells. This explains the failure of the numerous sepsis trials conducted with agents that block the inflammatory cascade, leading investigators to question whether death in patients with sepsis results from uncontrolled inflammation. Three autopsy studies of patients who died of sepsis have confirmed findings in animal models by showing massive loss of T and B lymphocytes and dendritic cells.

“Based on this study, rhIL-7 appears to be a particularly attractive therapy for this indication because it ameliorates many of the key pathophysiologic processes that are believed to be central to the lethality of sepsis,” said Richard S. Hotchkiss, MD, Department of Anesthesiology, Washington University School of Medicine and lead investigator on the study. “Specifically, rhIL-7 blocks sepsis-induced depletion of CD4 and CD8 cells, enhances lymphocyte recruitment, prevents the sepsis-induced loss in immunity as evidenced by preserved delayed-type hypersensitivity response, does not exacerbate the proinflammatory response in sepsis, and clearly improves survival.”

By demonstrating that treatment with IL-7 reverses fundamental immunologic defects in sepsis, this study is relevant to treatment approaches in other patient populations where acute lymphopenia is a critical symptom. As described in a seminal paper by Brenchley JM (2006)¹, during HIV infection, just as in sepsis, amounts of microbial products and inflammatory cytokines are increased in the patient’s bloodstream due to gut bacterial “seepage” from a compromised GI tract. In addition to direct viral damage, this condition is associated with systemic immune activation, which induces T cell dysfunction contributing to the apoptotic effects and accompanying marked decline in CD4 T cell numbers during HIV infection. This is a strong argument for therapeutic strategies aimed at repairing the gut mucosal damage and preventing microbial translocation and hyperimmune activation in the treatment of both HIV and sepsis patients.

“In their rationale for the use of IL-7 in treatment of sepsis, Unsinger J et al reinforce the same key pathogenesis mechanism supporting T cell activation in HIV-infected, HAART treated, Immune Non Responding (INR) patients who have been the subject of ongoing clinical investigations utilizing rhIL-7,” said Michel Morre, DVM, President and CEO of Cytheris. “This mechanism is directly linked to the persistent mini sepsis originating in the T cell depleted gut mucosa of the INR population and the fact that IL-7 not only repopulates the mucosa, but also blocks a massive acute sepsis model as shown in the Journal of Immunology study, may help to explain a crucial element in the clinical outcome in this specific HIV patient subpopulation.”