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In Utero Exposure to Foreign Antigens Causes Sensitization Rather Than Tolerance InductionIn Utero Exposure to Foreign Antigens Causes Sensitization Rather Than Tolerance Induction

Jeng-Chang Chen, MD, PhD1 and Ming-Ling Kuo, PhD2Jeng-Chang Chen, MD, PhD1 and Ming-Ling Kuo, PhD2

EAP2013European Academy of Paediatrics Educational Congress &

MasterCourse 19-22 September, 2013, Lyon, France

Chang Gung Children's HospitalTaoyuan, Taiwan

1Department of Surgery, Chang Gung Children's Hospital, College of Medicine, Chang Gung University, Taiwan

2Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taiwan

Actively acquired toleranceby P.B. Medawar

In utero donor cell injection

An encounter with foreign antigens before full development of immune system causes tolerance.

Donor skin transplant Third-party skin transplant

Donor-specific skin tolerance Donor-specific skin tolerance

Post skin transplant 4 months

Transuterine injection of B6 marrows into gestational day 14FVB/N fetal peritoneum

What if in utero exposure to allergens?What if in utero exposure to allergens?

Are FVB/N mice allergic to OVA?Are FVB/N mice allergic to OVA?

Adult FVB/N Sensitization Protocol:Adult FVB/N Sensitization Protocol:

AHR(D29) Sacrifice(D30)

I.P.: OVA 50μg + 0.8mg Al(OH)3 in NS,200μl/mouse I.H.: 2%OVA, 20 min

FVB/N adults are sensitive to OVA!FVB/N adults are sensitive to OVA!

Our attempt to desensitize allergen in uteroOur attempt to desensitize allergen in utero

AHR(D29) Sacrifice(D30)I.P.: OVA 50μg + 0.8mg Al(OH)3 in NS,200μl/mouse I.H.: 2%OVA, 20 min

Postnatally, mice were tested for their resistance to adulthood OVA sensitization by evaluating their humoral and cellular immunological profiles.

FVB/N mating, x

GA 14-day fetuses subjected to intraperitoneal injection of 50 g OVA

F1 subjected to adulthood sensitization protocol at 1 m/o as before:

Anaphylactic shock following 1st IP OVAAnaphylactic shock following 1st IP OVA

Lung pathology of anaphylaxisLung pathology of anaphylaxis

In utero sensitization demanded a threshold OVA dose!

In utero sensitization demanded a threshold OVA dose!

In utero sensitization to Der P2In utero sensitization to Der P2

Th2 skewed lymphocytes in mice with OVA-IgEproduction

Th2 skewed lymphocytes in mice with OVA-IgEproduction

In vitro culture

The lack of tolerance to OVA in mice without significant OVA-IgE production

How about postnatal OVA inhalation in prenatally OVA sensitized mice?

Boosting of allergic responses

Increased airway resistance

Airway inflammation and desquamationfollowing IU OVA & postnatal IH OVA

HE staining

Goblet cell metaplasia and collagenosisfollowing IU OVA & postnatal IH OVA

PAS staining Masson’s trichrome staining

Conclusion……

• Prenatal exposure to foreign antigens is not always a tolerogenic event.

The phenomenon of in utero sensitization suggested….

Prenatal allergen exposure facilitated postnatal allergic responses.

The phenomenon of in utero sensitization suggested….

Prenatal allergen exposure facilitated postnatal allergic responses.

The seed of asthmatic diathesis may be sowed early in utero! The seed of asthmatic diathesis may be sowed early in utero!