Neonates are more susceptible than adults to a variety of infectious diseases including bacterial, viral, and fungal infections, and human infants respond poorly to vaccination. Although this has been attributed to """"""""immaturity"""""""" of the immune system, little is known regarding the development of cellular and humoral immune responses in neonatal humans or nonhuman primates. Sequential development of immune tissues is difficult to examine in humans, so here we will track the development of immune cells and responses of neonatal macaques from birth through adolescence for comparison with adults. Our prior macaque studies suggest the newborn primate mucosal immune system is much more developed and competent, and develops at a faster rate than the systemic immune system. Further, recent discoveries of key regulatory cells including Th17 and Treg cells that stimulate or suppress immune responses respectively may develop at different rates in mucosal and systemic tissues of neonates, and may affect the way infants respond to immunization or infection. We hypothesize that sequential development of key regulatory immune cells occurs in normal neonatal tissues, particularly in mucosal sites, as these are more frequently exposed to environmental antigens. Since the mucosal immune system is more developed at birth, we also hypothesize that mucosal immunization strategies may result in improved vaccine responses in newborns and neonates. To test these hypotheses, we will examine and compare the emergence and development of CD4+ Th1, Th2, Treg, and Th17 cells, CD8+ T cells, B, NK and antigen presenting cells (APC), their na?ve/memory status, activation, and homing receptor expression, in both mucosal and systemic lymphoid tissue compartments of developing infants for comparison with adults. Soluble mediators including cytokines, chemokines, and antibody production will be quantified in plasma, mucosal secretions, and cell supernatants at different stages of development. Finally, cellular and humoral immune responses will be compared between infants vaccinated mucosally and systemically, and at different stages of neonatal development to optimize immunization strategies for infants. Immune responses to primary and secondary immunizations will be compared to determine whether mucosal vaccinations result in superior vaccine responses over systemically immunized macaques. Combined, these studies may explain many of the mysteries of neonatal immunology, and will have profound significance for human pediatric vaccination strategies.

Public Health Relevance

This proposed work will examine and compare the sequential development and functionality of both cellular and humoral immune systems in mucosal and systemic lymphoid tissues of nonhuman primates of different ages, and compare immune responses to mucosal and systemic vaccination of infants at different stages of neonatal development. These studies will determine whether mucosal vaccination results in improved vaccine responses in newborn or infant children and will have profound significance towards understanding neonatal responses to infection, immunization, and for optimizing human pediatric vaccination strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Prabhudas, Mercy R
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Tulane University
Schools of Medicine
New Orleans
United States
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Xu, Huanbin; Ziani, Widade; Shao, Jiasheng et al. (2018) Impaired Development and Expansion of Germinal Center Follicular Th Cells in Simian Immunodeficiency Virus-Infected Neonatal Macaques. J Immunol 201:1994-2003
Wang, Xiaolei; Xu, Huanbin (2018) Potential Epigenetic Regulation in the Germinal Center Reaction of Lymphoid Tissues in HIV/SIV Infection. Front Immunol 9:159
Dudley, Dawn M; Van Rompay, Koen K; Coffey, Lark L et al. (2018) Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. Nat Med 24:1104-1107
Veazey, Ronald S; Lu, Yingjie; Xu, Huanbin et al. (2018) Maternal antibodies against tetanus toxoid do not inhibit potency of antibody responses to autologous antigen in newborn rhesus monkeys. J Med Primatol 47:35-39
Wang, Xiaolei; Ziani, Widade; Xu, Huanbin (2016) Changes in Follicular CD4+ T Helper Cells as a Marker for Evaluating Disease Progression in the Competition between HIV and Host Immunity. Front Immunol 7:474
Xu, Huanbin; Wang, Xiaolei; Malam, Naomi et al. (2016) Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells. J Virol 90:1578-87
Brogdon, Jessica; Ziani, Widade; Wang, Xiaolei et al. (2016) In vitro effects of the small-molecule protein kinase C agonists on HIV latency reactivation. Sci Rep 6:39032
Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A et al. (2015) Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus-infected macaques. FASEB J 29:5072-80
Shen, Chanjuan; Xu, Huanbin; Alvarez, Xavier et al. (2015) Reduced expression of CD27 by collagenase treatment: implications for interpreting b cell data in tissues. PLoS One 10:e0116667
Xu, Huanbin; Wang, Xiaolei; Malam, Naomi et al. (2015) Persistent Simian Immunodeficiency Virus Infection Causes Ultimate Depletion of Follicular Th Cells in AIDS. J Immunol 195:4351-7

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