This application outlines a career development plan for the applicant, a practicing neonatologist who has a longstanding interest in understanding the features of the developing immune system that contribute to the increased susceptibility to infection and whose goal is to become an independent investigator. Under the mentorship of an established physician-scientist investigator and a multidisciplinary advisory committee, the P.I. will pursue a program of education (coursework, conferences, seminars) and a research project addressing the cellular and molecular mechanisms of ontogeny of humoral immunity. Studies in a variety of vertebrate species have documented that the ability to respond to specific antigens is acquired in a controlled, stepwise fashion during the development of the fetus, the infant, and the child. As a product of this normal pattern of development, infants and young children are unable to mount an effective humoral immune response against a number of pathogens that offer minimal difficulties to normal adults. Immunologic naivete, immature patterns of cytokine production and response, and genetic restrictions on the diversity of T cell receptor (TCR) and immunoglobulin repertoires have all been proposed as the mechanisms that underlie the physiologic immunodeficiency of the newborn infant. We propose to test the hypothesis that it is the limitation in the diversity of the T cell and B cell antigen receptor repertoires that serves as the primary determinant in the delayed acquisition of humoral immunity in the newborn infant. The proposed experiments will utilize a murine model wherein either the B cell or the T cell antigen receptor repertoires, or both, can be constrained to mimic major aspects of the neonatal repertoire, thus enabling us to determine whether such limitations will influence the normal acquisition of the humoral immune response. The focus is a restriction in the diversity of the third hypervariable region (CDR3) of the Ig H chain and the TCRalpha, beta, gamma and delta chains, which represents a major mechanism of fetal and neonatal repertoire limitation that is shared between human and mouse.
The aims of the study are to determine the hierarchy of acquisition of humoral responsiveness to model antigens in adult mice that have received lymphocyte precursors that are constrained to express only fetal-like CDR3 repertoires or prevented from expressing a normal fetal or adult immunoglobulin HCDR3 repertoire, and to delineate the separate roles played by B and T cells in controlling the programmed acquisition of the ability to respond to antigens during ontogeny. Since the mammalian immune system is not completely functional during fetal life, or even at birth, but undergoes a gradual maturation that is ordinarily not complete until some time during the neonatal period, we submit that the experiments outlined in this application have the potential to answer a number of questions of fundamental significance to the study of humoral immune responsiveness during ontogeny.
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