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A rodent model of in utero chimeric tolerance induction
1Department of Cardiothoracic Surgery, Stanford University Medical Center, California 94305-5247, USA.
Summary
In utero exposure to fetal liver cells can induce tolerance to heart transplants in rats. This method shows promise for pediatric transplantation by enhancing immune tolerance.
Area of Science:
- Immunology
- Transplantation Biology
- Developmental Immunology
Background:
- In utero tolerance induction is a promising strategy for pediatric heart transplantation.
- Fetal immune systems may be more receptive to tolerance induction before full immunocompetence develops.
- Mechanisms underlying fetal immunotolerance remain largely undefined.
Purpose of the Study:
- To investigate the induction of allogeneic tolerance in utero using donor-strain fetal liver cells.
- To assess the efficacy of fetal liver cells in inducing tolerance to both skin and cardiac allografts in a rat model.
- To explore the role of hematopoietic stem cell engraftment and immune cell populations in tolerance induction.
Main Methods:
- Lewis rat fetuses were inoculated with ACI rat fetal liver cells at 18 days gestation.
- Neonates received ACI skin and/or cardiac allografts.
- Control groups received saline or no inoculum.
- Graft survival was monitored, and immune responses were assessed via limiting dilution analysis and flow cytometry for chimerism.
Main Results:
- Tolerance to both skin and cardiac allografts was achieved in 28% of recipients inoculated with fetal liver cells and receiving both grafts.
- A marked reduction in precursor cytotoxic T-lymphocytes was observed in tolerant recipients.
- Significant splenocyte chimerism was detected in tolerant rats, suggesting hematopoietic stem cell engraftment.
Conclusions:
- Allogeneic tolerance to rat skin and heart tissue can be induced in utero using donor-strain fetal liver cells.
- This method offers a higher tolerance frequency with a lower cell inoculum and abortion rate compared to adult splenocytes.
- The requirement for both fetal liver cells and neonatal skin grafts suggests a critical window for hematopoietic 'education' during stem cell engraftment.