We have defined three profound defects regarding the ability of neonatal humans and mice to respond to herpes simplex virus (HSV) infection. These include 1) an inability to destroy viral- infected cells in the presence of antibody (antibody-dependent cellular cytotoxicity-ADCC) in vitro, 2) a related defect in the inability of human neonatal cells in the presence of antibody to protect neonatal mice from HSV infection, (ADCC in vitro, and 3) an inability to generate ADCC-mediating antiviral antibody after HSV challenge (a combined macrophage, T-lymphokine-dependent defect). We hypothesize that these ADCC antibody production and effector cell defects are central to the poor outcome of neonatal HSV infection. Reconstitution of these defects will change the mortality of HSV infection. These murine models act as in vivo """"""""test tubes"""""""" of human resistance factors against HSV infection. In this resubmitted proposal the murine and human antibody production defect will be further characterized (neutralization, ELISA), and the ontogeny of adult syngeneic T cell and macrophage reconstitution will be defined. The role of these cells and soluble replacing factors will be probed, with particular attention to human soluble factors from adults and neonates. Finally the antibody reconstitution will be correlated with survival. Preliminary experiments have demonstrated that both neonatal murine and human lymphocyte are unable to provide the necessary T-cell dependent lymphokine which reconstitutes antibody production and resistance to lethal neonatal HSV infection in combination with syngeneic macrophages. The ADCC effector defect will also be further characterized in vivo (human to mouse adoptive transfer) by analysis of the effector cell, the antibody type and target, the role of LFA- 1/OKM-1 adhesive glycoproteins, viral restriction, and finally the reconstitution of human neonatal effector function by stepwise immunomodulation o the adhesive and lytic defects. Both models (ADCC antibody production and effector cell reconstitution) will be extended from one of prophylaxis to one of therapy. Achievement of these goals of reconstitution of the neonatal defects will provide a logical step towards reduction of mortality of neonatal HSV infection in humans.
Showing the most recent 10 out of 13 publications
