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Compromised allograft rejection response in transgenic mice expressing antisense sequences to retinoic acid receptor
1Louis-Charles Simard Research Center, Notre-Dame Hospital, University of Montreal, Quebec, Canada.
Abstract:
Transgenic mice expressing antisense sequences to retinoic acid receptor beta2 (AS-RARbeta2 mice) were generated. The transgene was expressed in T cells, macrophages, and non-T spleen cells. These AS-RARbeta2 mice had four- to sevenfold higher endogenous RARbeta2 messages in their macrophages, comparing with their nontransgenic littermates, but the RARbeta protein level was significantly lower in these cells. This suggests that the antisense message interferes with RARbeta2 translation, and there is a feedback control of the RARbeta2 mRNA level in the macrophages. The endogenous RARbeta2 message was not detectable in T and B cells of either the transgenic or nontransgenic mice. These mice appeared to be healthy upon visual inspection. When transplanted with allogenic cardiac grafts heterotopically, the mice showed significantly compromised rejection response. These mice had a decrease of the macrophage population in spleen, using the nontransgenic littermates as references. The generation of alloantigen-specific T cell cytotoxicity was decreased in these AS-RARbeta2 mice. These results suggest that macrophage development and T cell function are affected by antisense expression of RARbeta2, and that anomaly in these cells might be contributing factors to the compromised immune response observed in the AS-RARbeta2 mice.
Insights
Antisense expression of retinoic acid receptor beta2 (RARbeta2) in mice impairs macrophage development and T cell function, leading to a weaker immune response and compromised organ transplant rejection. This highlights RARbeta2
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Retinoic acid receptors (RARs) play crucial roles in cellular differentiation and immune function.
- The specific role of RARbeta2 in immune cell regulation and transplant rejection remains incompletely understood.
Purpose of the Study:
- To investigate the impact of antisense-mediated inhibition of retinoic acid receptor beta2 (RARbeta2) on immune responses in transgenic mice.
- To determine the effects of RARbeta2 modulation on macrophage populations and T cell cytotoxicity.
Main Methods:
- Generation of transgenic mice expressing antisense sequences to RARbeta2 (AS-RARbeta2 mice).
- Analysis of RARbeta2 mRNA and protein levels in macrophages and T cells.
- Assessment of allogeneic cardiac graft rejection response.
- Quantification of macrophage populations and alloantigen-specific T cell cytotoxicity.
Main Results:
- AS-RARbeta2 mice exhibited reduced RARbeta2 protein levels in macrophages despite increased mRNA, suggesting translational interference and feedback regulation.
- These mice showed significantly compromised rejection of allogeneic cardiac grafts.
- A decrease in splenic macrophage populations and reduced alloantigen-specific T cell cytotoxicity were observed in AS-RARbeta2 mice.
- Endogenous RARbeta2 message was undetectable in T and B cells.
Conclusions:
- Antisense expression of RARbeta2 affects macrophage development and T cell function.
- Modulation of RARbeta2 influences immune cell populations and effector functions, impacting transplant rejection.
- These findings suggest RARbeta2 plays a role in regulating immune responses relevant to transplantation.