Immune responses in neonates are often poor. As a result, neonates succumb to infections and diseases which seldom affect adults. The deficient immunity of neonates is associated with poor Th1 function. Because Th1 function is centrally important in cellular immune responses, a clear understanding of the dysregulation of Th1 lineage cells in neonates must be achieved to devise strategies leading to the prevention and treatment of disease in early life. This proposal aims to identify the cellular and biochemical mechanisms governing poor Th1 function in neonates in situ.
Specific Aims 1 and 2 focus on the inability of neonates to develop mature Th1 memory responses.
Specific Aim 3 will concentrate on the failure of neonates to generate enhanced primary Th1 responses when antigen is delivered in adjuvant.
Specific Aim 1 will test the hypothesis that the inability to generate Th1 dominant memory is due to developmental immaturity in both neonatal T cells and non-T cells. This will be tested by physically separating the two compartments in chimeric mice in vivo: the capacity of neonatal T cells to develop mature Th1 memory in adoptive adult TCRbeta-deficient hosts will be assessed; conversely, the capacity of neonatal TCRbeta-deficient hosts to support mature Th1 memory development by adult T cells will be examined. The ability of neonatal T cells to develop mature Th1 memory when antigen is delivered to intact neonates by mature adult dendritic cells will also be investigated. Lastly, whether neonatal transgenic T cells bearing mature, adult-derived TCR are able to achieve mature Th1 memory in situ, in adoptively transferred normal neonates, will be tested.
Specific Aim 2 will test the hypothesis that poor Th1 memory results from the preferential survival of Th2 cells due to developmental immaturity in the endogenous cytokine milieu. The frequencies of antigen-specific Th1 vs Th2 cells in neonates and adults will be measured following primary and secondary immunization. The antigen-driven production of proinflammatory cytokines known to modulate T cell development, function, and survival will be compared in immunized neonates and adults. Lastly, the capacity of exogenously administered IL-2 and/or proinflammatory cytokines to influence Th1 memory development in neonates will be assessed.
Specific Aim 3 will test the hypothesis that the failure of neonates to respond to adjuvant with increased primary Th1 activity is due to limited function within the APC compartment. First, the contributions of the innate properties of the neonatal T cell and non-T cell compartments to poor responsiveness to adjuvant will be assessed: neonatal T cells will be transferred to adult TCRbeta-deficient hosts, and vice versa, and primary Th1 responses to antigen in adjuvant will be assessed. Second, the adjuvant-induced upregulation of two major Th1-promoting cytokines, IL-12 and IL- 18, will be compared in intact neonates and adults. Finally, the capacity of coadministered IL-12 and IL-18 to enhance adjuvant- induced primary Th1 function in neonates will be tested.
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