Characterizing the Protective Human Immune Response to Adenovirus

Cliona Rooney, Ph.D.

Baylor College of Medicine

Funded in March, 2002: $35000 for 1 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . SELECTED PUBLICATIONS .

LAY SUMMARY

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Characterizing the Protective Human Immune Response to Adenovirus

Adenoviruses are major causes of morbidity and death in patients who have weakened immune systems. These include people who have had transplants and take medicines to prevent the body's immune system from rejecting the transplanted tissue, and people with AIDS. To date, no antiviral agents have been approved to treat Adenovirus. The researchers hypothesize that cytotoxic T lymphocytes (CTLs) have the capacity to prevent or treat Adenovirus infections in patients with reduced immune responses. CTLs are immune system T cells that recognize a virus that has infected a target cell or been ingested by the target cell.

Prior studies, including those by this researcher, have indicated that CTLs can successfully prevent and treat certain other virally-induced diseases. They have been effective, for instance, in treating diseases caused by Epstein Barr virus and cytomegalovirus in patients who have undergone stem cell transplantation and been given drugs to suppress their immune system to prevent the body from rejecting the transplanted cells. The researchers now plan to determine whether CTLs similarly can treat or prevent Adenovirus infections that occur in patients with weakened immune responses.

To explore this hypothesis, they first will determine the strength and specificity of immune responses to Adenovirus in the blood of healthy donors. They will expose the healthy blood samples to Adenovirus to activate those T cells that are specific to attacking the Adenovirus. Dr. Rooney has the tools to detect and enumerate these T cells.

Next, they will determine how these Adenovirus-specific CTLs function to fight the virus, by looking for the gene product that the Adenovirus expresses for recognition by the CTLs. Then, the investigators will determine whether these CTLs can be expanded for eventual use as infusions of Adenovirus-specific CTLs. This is expected to improve immune function and decrease the amount of Adenovirus in patients who have had allogenic stem cell transplantation. This transplantation is increasingly being used for the treatment of malignant diseases, such as certain leukemias and lymphomas in immune deficiency diseases and in inherited bone diseases, such as thalassemia.

ABSTRACT

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Characterizing the Protective Human Immune Response to Adenovirus

Adenoviruses (Ads) are an important cause of morbidity and mortality in the immunocompromised host. The incidence of severe Ad disease in pediatrics is increasing in association with growing numbers of immunocompromised children, where case fatality rates as high as 50% to 80% have been reported. There are no approved antiviral agents with proven efficacy for the treatment of severe Ad disease, nor are there any prospective randomized, controlled trials of potentially useful anti-Ad therapies. Virus-specific CTL have proved successful in the prevention and treatment of EBV and CMV-associated diseases in hematopoietic stem cell recipients and we hypothesize that Ad-specific CTL will also be effective for the treatment of Ad infections 3, 4, 5. Immune intervention for virus-associated diseases requires detailed knowledge of the immune control of the virus in question. However, little is known about human immune responses to Ads. Immunodominant viral target antigens have not been identified, the importance of CTL specific for different Ad antigens for control of disease are unknown, and few immunological reagents such as peptide epitopes or tetramers for the study of Ad infections have been described. We plan to characterize the function and antigen-specificity of Ad-specific CTLs and to generate peptide and tertramer reagents for studying the fine specificity of the Ad-specific immune response. We will then determine the ability of Ad-specific CTL lines to reconstitute immune responses and to have anti-viral effects in SCT recipients, using the identified peptides and tetramers to compare immune responses before and after CTL infusion.

INVESTIGATOR BIOGRAPHIES

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Cliona Rooney, Ph.D.

Cliona M. Rooney, Ph.D., is a Professor in the Hematology/Oncology Section, Department of Pediatrics at Baylor College of Medicine, and a member of the Shell Center for Cell and Gene Therapy. She holds a joint appointment in the Division of Molecular Virology and Microbiology. Her laboratory focuses on the use of antigen-specific cytotoxic T lymphocytes (CTLs) to prevent and treat virus-associated diseases and malignancies and methods for overcoming tumor-immune evasion strategies.

Prior to joining the faculty at Baylor College of Medicine, in January of 1998, Dr. Rooney was an Associate Professor, Department of Virology and Molecular Biology, at St. Jude Children's Research Hospital. Dr. Rooney earned a Ph.D. degree in Immunology from the University of Cambridge, England. She received postdoctoral training at the Universities of Bristol (Department of Pathology) and Birmingham, Department of Cancer Studies, from 1981-85 and at Yale University School of Medicine from 1985-87.

SELECTED PUBLICATIONS

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Leen A. M., Ratnayake M., Foster A. E., Heym K., Ahmed N., Rooney C. M., and Gottschalk S.   Contact activated monocytes: efficient antigen presenting cells for the stimulation of antigen-specific T cells.   J Immunother. 2007 Jan;30(1):96-107.

Leen A. M., Myers G.D., Sili U., Huls M.H., Weiss H., Leung K.S., Carrum G., Krance R.A., Chang C.C., Molldrem J.J., Gee A.P., Brenner M.K., Heslop H.E., Rooney C.M., and Bollard C.M.   Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals.  Nat Med. 2006 Oct;12(10):1160-6.

Leen A. M., Sili U., Vanin E. F., Jewell A. M., Xie W., Vignali D., Piedra P. A., Brenner M. K., and Rooney C. M.  Conserved CTL epitopes on the adenovirus hexon protein expand subgroup cross-reactive and subgroup-specific CD8+ T cells.  Blood 2004 Oct 15;104(8):2432-40.

Leen A. M., Sili U., Savoldo B., Jewell A. M., Piedra P. A., Brenner M. K., and Rooney C. M.   Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications.  Blood. 2004 Feb 1;103(3):1011-9.