Exploration of Allograft Humoral Rejection in Chronic Histiocytic Intervillositis

Study Overview
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Brief Summary
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Chronic histiocytic intervillositis (CHI) is a rare condition with an incidence of 5 in 10,000 pregnancies. This rare condition is associated with placental inflammatory lesions leading to severe and recurrent obstetrical complications: intrauterine growth retardation (IUGR), fetal death in utero and miscarriage. The pathophysiological mechanisms of CHI are poorly understood, while the empirical treatments prescribed to prevent recurrence are cumbersome and of poor efficacy. Recent findings suggest that an alloimmune response may play a role. In a recent work, the investigators have demonstrated the role of maternal alloantibodies directed against fetal HLA antigens in two patients followed for recurrent IUGR associated with CHI. Their work suggests that a humoral alloimmune response directed against fetal HLA antigens mimics an allograft rejection process. The investigators propose to extend the preliminary results obtained in these patients to provide new insights into the pathophysiological mechanisms of CHI, and eventually to predict the risks of fetal loss.

Official Title
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Exploration of Allograft Humoral Rejection in Chronic Histiocytic Intervillositis

Conditions
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Chronic Histiocytic Intervillositis, Intrauterine Growth Retardation, Fetal Death in Utero, Miscarriage

Intervention / Treatment
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* Procedure: Biological collection


Participation Criteria
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Eligibility Criteria
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Family Inclusion Criteria: Mother and father ≥ 18 years old For mothers in the CHI group : History of a normal pregnancy (full term, alive child) or IUGR/MFIU or miscarriage(s) or abortion followed by at least 1 obstetrical complication such as IUGR, MFIU, miscarriage Diagnosis of chronic histiocytic intervillitis made by placental anatomopathological examination with CD68+ marking For the mothers of the antiphospholipid syndrom group History of miscarriage(s) Having an anti-phospholipid syndrome For mothers in the normal pregnancy group: Third consecutive pregnancy of normal course, at term (≥ 36 weeks of amenorrhea) with eutrophic child For the mother and father: o Consent to participate in the study and for the participation in the study of at least one child and/or the use of existing samples (placenta / fetal DNA) from at least one previous pregnancy with CHI for the CHI group or at least one previous miscarriage for the APS group For the father: o Father of the last pregnancy and of the child(ren) participating in the study Exlusion criteria : For mothers in the normal pregnancy group: o Suspected or confirmed intra-amniotic infection For all the mothers: History of blood transfusion History of allogeneic organ transplantation For the mother and the father: Person under legal protection (guardianship, curatorship)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient with chronic histiocytic intervillositis<br>Patient with CHI, as well as her children and their father. Blood collection from the parents, saliva collection (or blood collection) from the children, placenta collection | Procedure: Biological collection<br>* up to 25 mL of blood collection for the adults and saliva collection for the minor at inclusion, and placenta collection at childbirth<br>|
| Active Comparator: patients with anti-phospholipid syndromes (APS)<br>Patient with antiphospholipid syndrome, as well as her children and their father. Blood collection from the parents, saliva collection (or blood collection) from the children, placenta collection | Procedure: Biological collection<br>* up to 25 mL of blood collection for the adults and saliva collection for the minor at inclusion, and placenta collection at childbirth<br>|
| Placebo Comparator: women with a third full-term pregnancy without growth retardation.<br>Patient with normal pregnancies, as well as her children and their father. Blood collection from the parents, saliva collection (or blood collection) from the children, placenta collection | Procedure: Biological collection<br>* up to 25 mL of blood collection for the adults and saliva collection for the minor at inclusion, and placenta collection at childbirth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients diagnosed with CHI, defined by the concomitant presence of the 3 criteria required to evoke humoral alloimmune rejection for this pathology | Proportion of patients diagnosed with CHI, defined by the concomitant presence of the 3 criteria required to evoke humoral alloimmune rejection for this pathology, namely CD68+ infiltrate, AND C4d deposits on the trophoblastic villi AND the presence of at least one FSA (fetus-specific antibody, directed against fetal HLA antigens in the maternal blood) with an elevated level, defined by a Mean Fluorescence Intensity (MFI) > 10,000). This proportion of patients observed in CHI carriers will be compared to the proportion of patients with the concomitant presence of the same 3 criteria observed in the other two control groups. | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To measure the FSA levels by Mean Fluorescence Intensity for the different obstetrical complications: intrauterine growth retardation (IUGR), fetal death in utero and abortion for IUGR. |  | up to 6 months | 
| to measure the correlation between fetus-specific antibody level by Mean Fluorescence Intensity and the severity and/or precocity of obstetrical complications |  | up to 6 months | 
| measure of semi-quantitative graduation of C4d in placenta compared to percentage of villositis |  | up to 6 months | 
| measure of semi-quantitative graduation of CD68+ infiltrate in placenta compared to surface and number of involved villositis |  | up to 6 months | 
| To measure the expression of HLA class I and II molecules by placental villi by ß2-microglobulin and HLA-DR labelling |  | up to 6 months | 
| Epitope analysis with algorithm developped by laboratoire HLA de St Louis (Pr JL Taupin) | Epitope analysis with algorithm developped by laboratoire HLA de St Louis (Pr JL Taupin) to determine whether an antibody response against a limited number of epitopes present during a first pregnancy that resulted in a healthy child can explain immunization against both paternal alleles | up to 6 months |