Infant mortality from infectious diseases results in millions of deaths worldwide in infants younger than six months of age. Infants have a suppressed immune system which makes them highly vulnerable to infections and limits their immune responses to protective and life-saving vaccines. Monocytes in peripheral blood differentiate to macrophages and dendritic cells (DC) which drive adaptive immunity, and they also likely provide cytokine support for T-independent B cell responses. We have recently identified two populations of monocytes (CD14+) in cord blood, CD36hi and CD36lo and shown that the CD36hi monocytes drive development of regulatory T (Treg) cells. We hypothesize that the immunosuppressive state of infants is due in part to the predominance of these immunosuppressive CD36hi monocytes which promote expansion of Treg cells. We also hypothesize that during infancy, these cells respond poorly to innate immune signals and are unable to support T-independent (TI) B cell responses.
In Aim 1, we will examine the innate immune responses initiated by CD36hi monocytes to determine the extent to which innate immunity in infants is compromised by the immunosuppressive monocytes.
In Aim 2, we will monitor changes in the number and function of CD36hi monocytes during infancy and throughout childhood, and determine if they can be converted from promoting Treg cells to effector T cells by stimulating them with pathogen recognition receptor (PRR) agonists or by blocking binding of CD36 to TSP1, an activator of latent TGF-? which induces Treg cells;and in Aim 3, we will determine if the CD36hi monocytes are unable to support TI B cell responses and determine if treatment of these monocytes with PPR agonists can induce these cells to support TI B cell responses. Results from these studies are expected to provide a basis for overcoming the immunosuppressive state of infants by a combination of more effective vaccine adjuvants that will abrogate the immunosuppressive state of infants as well as enhance their immunity. A major deficiency of infants is their inability to generate TI B cell responses to polysaccharide antigens such as is required for immunity to Streptococcal pneumonia, and we expect the results will identify the means to induce infants to generate such life-saving immune responses.
This study focuses on subpopulations of monocytes that induce regulatory T cells and may be responsible for the immunocompromised state of infants. By seeking ways to reverse the immunosuppressive phenotype of these monocytes using the tools of innate immune responses, we expect to identify molecules that can be used as adjuvants to induce strong adaptive immune responses in infants.
|Wiethoff, Christopher M; Nemerow, Glen R (2015) Adenovirus membrane penetration: Tickling the tail of a sleeping dragon. Virology 479-480:591-9|
|Iwashima, Makio; Love, Robert (2013) Potential of targeting TGF-Î² for organ transplant patients. Future Med Chem 5:281-9|