Immunological Basis of SowFeedback Programs

Mriegndra Rajput, BVet, MS, PhDGastrointestinal Stress Biology Laboratory

Department of Large Animal Clinical Sciences,College of Veterinary Medicine, Michigan State University, East Lansing, MI

Introduction

• Basics of immunology• Differenced in Systemic vs mucosal immune system• How Mucosal immune system works • Challenges to induce mucosal immune response/ Mucosal Vaccines • Advantage of feedback program in inducing mucosal immunity

Complement

Innate Immunity Adaptive immunity

Microbes antimicrobial peptidesmucin

Epithelial barrier

Phagocytic cells

Complement

Cytokines

0 6 Hours 1 7 Days

Always present, Early defenseReady to recognize and destroyNot Specific No memory

Acquired by specific cells (lymphocytes)Takes about 4-7 days to generateSpecific Long lasting memory

Helps in activation Figure adopted and modified from www.nobelprize.org/educational/medicine/immunity/

Adaptive immunity: How it works

Figure adopted and modified from www.nobelprize.org/educational/medicine/immunity/

Cell mediated immunity

Humoral immunity

Systemic and mucosal immune systems are not same

ComplementComplement

Systemic immune system Mucosal immune system

Figures adopted and modified from The pig Site and Ito et al. 2015. Plastic and Reconstructive Surgery 136(2):297-304.

Barrier: SkinFunction of Skin: Barrier, immune activationActivation: Systemic protection

Barrier: Epithelial cell (intestine, Lung, urogenital)Function of Epithelia cell: Barrier, absorption, tolerance, immune activationActivation at one site: Provide protection to all mucosal surface

Mucosal immune system: multi tasker

• Intestine: Largest lymphoid organ, contain more immune cells then any other organ.

• Vast surface area: Constant exposure to commensal (at least 400 spp) and pathogenic microorganism.

• Intestinal Epithelial cells: anatomical and physiological barrier with primary absorptive function

• Synthesis of vitamin B, Vitamin K

Mucosal immune system: multi tasker

• Need to distinguish: food antigen, commensal and pathogenic bacteria.• Need to generate homeostatic balance: immune tolerance (food

antigen/ commensal bacteria) and immune response (pathogenic bacteria)

Mucosal immune system/GALT: How it works

• Can be divided:Physical barrier: Intestinal Epithelial cells (IEC)Immune induction site: Peyer's patchesEffector site: Lamina propria

Mucosal immune system/GALT: How it works

Figure adopted from Mowat. 2003. Nature Reviews Immunology 3, 331-341 and www.cals.ncsu.edu

Mucosal immune system/GALT: How it works

Figure adopted and modified from http://theibdimmunologist.com and Borei et al. 2016. European Respiratory Journal 47: 1244-1260;

Mucosal immune system: made for tolerance

• T cell in lamina propria-Greater threshold for activation, then peripheral T cells: produce higher concentration of cytokines upon activation

Mucosal immune system: made for tolerance

CD103+ DC induce tolerance (differentia T cell to FoxP3 T reg),

Antigen-Gut-portal vein- liver: sinusoidal endothelial cells, tolerogenic conventional dendritic cells (DCs) or plasmacytoid DCs (pDCs) absence of co-stimulation: Tolerance

Pabst et al. (2012) Mucosal immunol Nature 5, 232–239.

Mucosal Vaccine: Challenges

• Vaccine become diluted (mucosal secretions), • Captured in mucus gels, • Antigen degrade: proteases, nucleases, excluded by epithelial barriers• Difficult to determine exact dose crossing mucosa • Gut: Induce immune tolerance

Mucosal Vaccine: Current status

• Adhere to mucosal surfaces/M cells: Multimeric and/or particulate: adhere to mucosal surfaces (Microparticles, adherent gel-forming polymers).

• Breaching epithelial barrier: live pathogens (live attenuated poliovirus and live attenuated S. typhi: preferentially adhere to M cells).

• Activating mucosal immune system: AdjuvantsBacterial enterotoxins (Cholera toxin, Heat-labile toxin -LT) E.coli: diarrhea in humans.

• Due to safety: detoxifying E. coli LT (R192G), B subunit of cholera toxin (retrograde transport to the brain by olfactory nerves)

Neutra et a. 2006. Nature Reviews Immunology 6, 148-158

Mucosal Vaccine: Current status-Adjuvants

Cited in: Rhee et al. 2012; Clin Exp Vaccine Res. Jul; 1(1): 50–63.

Cytokines: IL-12, granulocyte/macrophage colony-stimulating factor (GM-CSF) or acombination

Feedback Programs advantage: Immune response

• Use live pathogen (natural adjuvant).• Use in sows (Immune system in well developed).• Pathogen in sufficient quantity/concentration: cross mucosa• Oral administration: Protection to all mucosal site (Oral, respiratory,

urogenital)• Most pathogen enter through mucosal route• Mucosal immune response: immunoglobulin- colostrum- newborn

piglets.• Commensal: Gut microbiota in neonates.

Acknowledgment

• Dr. Adam Moeser, Matilda R. Wilson Endowed Research Chair of Large Animal Clinical Sciences , Director of the Gastrointestinal Stress Biology Laboratory , Michigan State University, East Lansing.

• Dr. Robert Morrison, Department of Veterinary Population Medicine, CVM, University of Minnesota, MN.

• Agriculture and Food Research Initiative Competitive Grant No. 2017-67015-26673 from the USDA National Institute of Food and Agriculture (to A.J.M.).

Thanks