The hypothesis which underlies the predictions made in this application is that antigen specific T cell responses by newborns fail when the antigen presenting function of their mononuclear cells is blocked. The hypothesis is formulated to account for impaired immune responses which may follow neonatal blood transfusions or neonatal infection with herpes simplex virus, cytomegalovirus or rubella virus. The clinical model selected to test the predictions derived from the hypothesis is that of cutaneous and or CNS recurrences of herpes simplex virus (HSV) following a perinatal HSV infection. Approximately 1:2000 infants born in the USA is perinatally infected with HSV and this is a clinically important infection because the initial mortality is high and motor development is delayed in a subset of the survivors despite anti-viral treatment. We previously showed that the frequency of HSV-specific T cells measured in limiting dilution assays was low for 1 or more years in the subset of survivors who had cutaneous recurrences of the virus, but that the production of IgG 1 and 3 subclass antibodies to the virus was unimpaired. """"""""Clonal paralysis"""""""" is proposed as the mechanism to account for the delay in clonal expansion of HSV-specific T cells in these infants. Existing animal models indicate that clonal paralysis occurs as a consequence of antigen binding to T cells in the absence of helper factors. The studies proposed in this application will characterize the potential of T cells to be stimulated or paralyzed in vitro by T cell receptor ligation in cultures where the accessory cells have been preincubated with herpes simplex virus. Where HSV interferes with a response, the defective lymphokine will be characterized. These studies will be followed by an analysis of T cell phenotypes and alloantigen-specific response of T cells of infants who survived a neonatal HSV infection. The in vitro response of naive (CD45RA) and memory (CD45R0) T cell phenotypes will be measured separately.
The third aim will determine the duration of the deficient memory T cell response to HSV following neonatal infection and attempt to correlate this with the clinical course and frequency of recurrences in a prospective study. Responses to HSV will be quantitated by limiting dilution cultures and will be compared with healthy controls who were infected with HSV after the neonatal period. The results of these studies will be important because they will be the first systematic analysis of the potential for in vivo interference with T cell development, and the development of specific immunity, in a population of infants who are at risk for impaired CNS development.
Showing the most recent 10 out of 27 publications
