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| |  To develop new vaccines against some of the world's biggest killers, including HIV, malaria, and tuberculosis, scientists must be able to evaluate promising candidates. Some of the most promising potential vaccines, are made from weakened live versions of the infectious agent. As a result, they cannot be studied in human trials unless researchers can be confident that the weakened vaccines will be safe. Vaccine researchers need improved and reliable animal tests that can help them evaluate potential vaccines before they are tested in humans.
Dr. Flavell and his colleagues are working to genetically engineer laboratory mice whose immune systems are similar enough to humans to permit testing of vaccines against diseases that disproportionately affect people in the developing world.
The team is working with CD34+ transplanted Rag2-/- gammac-/- mice. Investigators have performed preliminary studies to determine the LD100 of Listeria in mice, and are now evaluating if human CD34+ cell transplanted Rag2-/-gammac-/- mice have an increased survival to this dose of Listeria.
In the mice infected with Epstein Barr Virus, investigators engaged in ongoing collaborative studies (L. Leoncini, Siena, Italy) are analyzing lymphoid tissue morphology, latency, and B cell immunoglobulin gene mutation status by single cell PCR in EBV infected cord blood cell-transplanted mice. Thus far data suggest that currently proposed mechanisms for EBV infection of the human immune system hold true in this preclinical in vivo model. |
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| | | Generate mice in which genes of the human immune system replace those of the mouse to aid engraftment and development of human cells and selection of a functional immune system | | | | | Validate the extent and distribution of expression of these genes | | | | | Use these mice as recipients of human hematopoietic stem cells (HSCs). Establish engraftment of the human lymphoid, myeloid, and other cell populations | | | | | Validate that the immune response obtained in these mice approximates the immune response of humans to antigens, pathogens and currently used vaccines | | |
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| | | Investigators have successfully generated Rag -/- IL2Rgamma -/- (Rag-/-gammac-/-) mice by targeting Balb/c x 129 ES cells. These cells have been further targeted with vectors to humanize the genes for the cytokines TPO, IL-3 /GM-CSF and M-CSF. | | | | | The mouse class I MHC H2-K gene has been targeted into the Rag, IL2Rgamma ES cells. The targeting vector is designed to humanize the peptide-binding exons of the class I H2-K gene using exons from the human HLA-A*02 allele. | | | | | Targeting constructs for a mouse MHC Class II knockout and a knockin of human HLA DR4 have been generated. | | | | | Mice with human immune genes have been analyzed for expression of the human cytokines. Following expansion, the mice will be used to transplant with human CD34+ Cord Blood hematopoietic stem cells. | | | | | Tested transplantation of human mesenchymal multipotent stroma cells (MSCs) into mice with the intention of using MSCs to provide human hematopoiesis and immune system supporting factors not readily available from the mouse background. They found that MSCs from cord blood and bone marrow express varying levels of hematopoiesis-supporting cytokines, and MSC supernatant supports human myeloid colony formation from stem and progenitor cells. | | | | | Investigators found that MSCs express certain toll-like receptors, and are capable of responding to pathogen-associated molecules with an increase in secretion of hematopoiesis-relevant cytokines. While human myelopoiesis seems to be supported in short-term in vivo assays, investigators have not yet consistently achieved long-term engraftment and maintenance of MSCs. | | | | | Demonstrated that CD34+ transplanted Rag2-/- gammac-/-mice can be infected with Epstein Barr Virus. | | |
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| | | Dr. Sean Stevens, Regeneron Pharmaceuticals, New York, United States - US | | | | | Dr. Markus G Manz, Institute for Research in Biomedicine, Bellinzona, Switzerland - CH | | |
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