Neonatal Immunology

Kristina Abel, PhDCNPRCUC Davis

How a Lymphomaniac views (IL)lness

Age-dependent differences in responses to human vaccines

1. Vaccine immunogenicity• antibody responses (titer, memory)

-infant > adult (polio, hepatitis B, malaria)

• T cell responses (cytokine secretion, function) - adult > children > infants- primed in infants, even in presence of

maternal Ab(measles, mumps)

2. Vaccine efficacy• BCG, malaria vaccines

- infants > children, low/no efficacy in adults

- protect against severe disease

Thus, adult vaccine responses are not reliable predictors of vaccine immunogenicity or efficacy in infants.

• Hematological changes in the first few months of life

naïve/ memoryT vs. B cellsT cell subsetsB cell development and maternal Ab

• Development of normal flora at mucosal sites

Implications for mucosal immune responses?

Influence of nutrition, including breast-feeding

• Immune system is immature -

Immune system is developing: differences in quality and quantity

Unique Features of the Neonatal Immune System

CD4+TEM Th1eff Antigen IL-2/ IFN-g CD4+TCM IL-12 IL-2 CD8+T CD8+Teff IFN-g Th0 Th1 prime IL-2/ IFN-g IL-2/ IFN-g CD8+TEM CD8+TCM

Treg

“Normal” Immune Response

CD4+TEM Th1eff Antigen IL-2/ IFN-g IL-23 CD4+TCM IL-12 IL-2 Th1 prime CD8+T CD8+Teff Th0 IFN-g IL-2/ IFN-g Th17 IL-2/ IFN-g Treg CD8+TEM CD8+TCM

Infant’s Immune Response

B Cell: Ab

• Determine developmental changes in immune cell populations on the phenotypic and functional level.

intracellular signaling pathwaysinfluence of mDC on T cell functiongeneration of multifunctional T cellsrelationship between positive and negative regulation of

T cell functioninduction and survival of memory T cells

• Apply knowledge to pediatric vaccine design.

dose-dependency timing: age factortesting of multiple routes and their combinationadjuvants/ DC primingmagnitude, quality and survival of memory T cell populations

• Analysis of pathogen and/or vaccine-induced immune responses in relation to normal developmental changes!

• Define early, local immune responses in tissues close to pathogen entry site.

Tasks

Rhesus Macaques

Design a novel oral pediatric combination vaccine using a

recombinant attenuated Mycobacterium tuberculosis vector

expressing SIV/HIV genes.

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Geographical Overlap between HIV and M.tb Infections

HIV

+

TB

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Neutra, Kozlowski -2006

Tonsillar M Cells - Target for Pediatric HIV Vaccine

Tonsil

Breast-milktransmission

Virus entry:

oral mucosa tonsil intestine

Braendtzaeg, 2003Vaccine, 21:3382

The Mammary Gland - Part of the Mucosal Immune System

Mammary gland -reflective of responsesin lung and GALT

- PP and tonsils are developed at birth, but GC lack for a few weeks

- mucosal immunity is passively acquired from the mother via breast milk

- breast -feeding is estimated to prevent up to 3 million death/ year in newborns

CTL

SLPI

Robertson, 2000.

Reviews Reprod., 5:164

Pregnancy - Induction of a Tolerogenic Milieu

IgG only!

Maternal Antibodies

Immunity transmitted from the Mother to the Fetus

0 4 8 12 16 20 24 28 32 36 40 44 480

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CD3+TCD20+B

Age (Weeks)

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100CD4+TCD8+T

Age (Weeks)0 4 8 12 16 20 24 28 32 36 40 44 48

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CD4+T/CD62LCD8+T/CD62LCD4+T/ CD95CD8+T/ CD95

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Changes in Lymphocyte Populations during the First Year

CD4+T CD8+T0

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Blood Spleen Mesenteric LN0

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