Congenital and neonatal infections with Herpesviruses, especially cytomegalovirus (CMV) and Herpes simplex viruses (HSV) are major causes of mortality and morbidity in the USA. Cytotoxic responses by blood mononuclear cells correlate with recovery from CMV infections in adults and immunity to other Herpesviruses is maintained by T cells. Lymphocytes from healthy newborns show little if any response to Herpesvirus antigens in vitro: this most likely reflects a low frequency of responder T cells in the human germ line repertoire. However T cells from babies with congenital CMV, who are immune as judged by antibody production, also respond little to CMV antigen and these patients continue to shed virus in the urine for years. Deficient immunity to Herpesviruses may account for the severity of these infections in newborns. This proposal therefore analyses the ability of monocytes from healthy newborns to process CMV and HSV antigens and the cellular basis for the impaired response to CMV in congenital CMV with particular regard to possible interference with monocyte or T cell function. We shall investigate the potential for anti-Herpes responses by normal newborn lymphocytes and the defects which may arise in newborn HSV types 1 and 2 infections. For comparison we will document the acquisition of Herpesvirus specific responses in healthy children. This dissection of the development of immunity to Herpesviruses is made possible through in vitro culture techniques using parent-child combinations where there is obligatory sharing of an HLA haplotype. These conditions satisfy the linkage requirements for antigen recognition by T cells and allow us to separate antigen processing by monocytes from helper cell induction and cytotoxic cell generation. To characterise the development of virus specific responses the frequencies of responder T cells at different ages will be determined by limiting dilution. The main purpose of the study is to obtain basic information from infected infants from which treatment strategies for congenital infection (and especially CMV) could be devised. One treatment modality which might be envisaged fpr tje future could be the transfusion of parental, CMV-specific, non-alloreactive, T cell blasts into an affected infant. To determine whethr such a procedure would be either safe or effective one would first need to demonstrate that parental T cells could indeed be depleted for alloreactivity and that they could express useful anti-viral activity.
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