Measles remains an important cause of infant mortality yet little is known about the immunobiology of this organism. Questions of immunopathogenesis underlie all of the problems we currently seek to understand including disruption of normal immune function, waning immunity after vaccination and most recently the association between high titer measles vaccines and an increased risk of mortality. There is an urgent need for basic studies of the immune response to measles in order to better understand the capacity of this virus to interact with and influence the human immune system. In the first part of this study, 120 children undergoing routine measles vaccination will be recruited and a battery of standard and novel immunologic assays will be performed. Several novel assays of measles- specific cellular responses will be used to examine the balance between humoral and cellular responses and to test the hypothesis that measles virus induces a predominantly T helper2 response (ie: antibody production favored over cellular responses). A-says of humoral response will include standard plaque neutralization and IgM and IgG titers as well as measles- specific IgA, IgE and IgG subclass determinations. These measures will be correlated with measles-specific lymphoproliferation as well as cytokine production and mRNA expression in isolated PBMC. The vaccine-induced responses will be compared with data already available from previous studies in measles patients and with the results of selected parallel studies in children with natural infection. The identification of differences between the immune responses generated by wild-type and vaccine-strain virus is essential if the limitations of currently available vaccines are to be understood. In the second part of the study possible mechanisms of measles-induced immune cell injury will be explored. The PBMC sublet infected with measles virus after vaccination will be identified using reverse-transcriptase PCR. The cytokine production of measles-specific CTL clones will be analyzed to determine if memory for measles is retained preferentially in cells biased to respond in a Th2 fashion. The role of apoptosis (programmed cell death) in the measles-induces disruption of normal immune function will be explored by infecting cord blood infant and adult lymphocytes in vitro. The potential for vitamin A to protect against measles-associated apoptosis will be assessed in vitro as well as in children treated with vitamin A during acute measles infection. Finally. the possibility that measles may have a superantigen-like activity will be addressed by challenging cord blood lympohocytes with measles antigens in vitro. These mechanisms need not be mutually exclusive and the potential for interaction is large. Furthermore each of these mechanisms can be plausibly linked to the Th2 predominant response to measles which may be central to understanding the immunologic abnormalities associated with measles infection and measles vaccination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035137-02
Application #
2070571
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1993-09-30
Project End
1997-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Montreal General Hospital
Department
Type
DUNS #
City
Montreal
State
PQ
Country
Canada
Zip Code