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NK Cell Responses to EBV <br/><br/>Natural killer (NK) are regarded as critical in the early immune response to EBV, but their role in controlling expansion of infected B cells is not understood. Our studies using computational cellular deconvolution approaches of public gene array data sets indicate that NK cells are increased in EBV+ PTLD tumor lesions, and in vitro studies demonstrate that NKG2A+ is expressed on NK cells which recognize and kill autologous EBV-infected B cells. Further, the non-classical MHC molecule, HLA-E, the ligand for NKG2A, is expressed on EBV+ B cell lymphoma lines and peptides from EBV latent cycle proteins can bind to HLA-E. We suggest that NKG2A+ NK cells recognize and respond to EBV+ B cells, and that NKG2A functions as a checkpoint molecule. Further, we predict that targeting the NKG2A/HLA-E interaction can potentiate the ability of NKG2A+ immune cells to mediate cytotoxicity against EBV+ B cell lymphomas. Current projects include: 1) Determining the influence of EBV peptide binding to HLA-E in the reactivity of NKG2A+ NK cells, determining the natural peptidome for HLA-E expressed on EBV+ B cell lymphoma lines. 2) Establishing the phenotype and function of NKG2A+ NK cells & NKG2A+ T cells in patients who develop EBV+ PTLD using patient samples and mass cytometry (CyTOF). We anticipate these studies will yield a new understanding of the immune response to EBVs, will increase our knowledge of the regulation and function of NKG2A+ immune cells, and will provide the basis of innovative and much needed therapeutic approaches for EBV+ PTLD and other EBV-associated malignancies.<br/><br/>Exosomes in Immune Responses<br/><br/>Solid organ transplantation is currently the treatment of choice for children with a variety of end-stage organ diseases. The success of clinical transplantation is dependent on the use of potent immunosuppressive drugs to prevent rejection of the allograft. However, even with our arsenal of immunosuppressive agents, nearly half of pediatric transplant recipients will have a rejection episode in the first-year post-transplant. Clearly, acute rejection remains a major hurdle in pediatric solid organ transplantation. Exosomes are nanometric (50-150nm) membrane vesicles that are released, into blood and other body fluids, by most cell types and can transfer cytosolic proteins and nucleic acids. We have shown thatt exosomes contain and transfer microRNAs (miRs) between cells that allow for local and distant intercellular communication. MicroRNAs,short non-coding RNA molecules can post-transcriptionally regulate messenger RNA transcripts, resulting in translational repression. On going projects are focused on sequencing the exosome miRNome, analyze TCR and immunoglobulin heavy chain repertoires, and a multi-parameter analysis of the alloimmune response by mass cytometry with the goal of identifying biomarkers associated with and predictive of graft outcomes. <br/><br/>Plasmacytoid Dendritic Cell-Mediated Graft Prolongation <br/><br/>Dendritic cells (DCs) are antigen-presenting cells (APCs) important for initiating and coordinating the immune response. Plasmacytoid dendritic cells (pDCs) are a subset of DCs and multiple studies report a tolerogenic phenotype of immature pDCs. Using experimental models of transplantation, our studies demonstrate that f donor pDCs prolongs allograft survival. To determine factors unique to the tolerogenic phenotype of pDCs we performed a microRNA (miRNA) microarray, and our results show that the miR-181 family of miRNAs is increased in pDCs. Likewise, pDCs deficient in miR-181a fail to prolong allograft survival. Semaphorin 4a, which is involved in immunomodulation and is required for the function and stability of regulatory T (Treg) cells, is decreased in miR-181 deficient pDCs. Together our results show a critical role for miR-181 regulating the tolerogenic potential of pDCs and additional studies will are focused on developing novel therapeutics for graft prolongation.
Biomarkers for Post-Transplant Lymphoproliferative Disorders in Children
Solid organ transplantation is an important therapeutic option for children with a variety of
end stage diseases. However, the same immunosuppressive medications that are required to
prevent the child's immune system from attacking and rejecting the transplanted organ can
predispose these individuals to developing a very serious cancer that is linked to
Epstein-Barr virus (EBV).
Stanford is currently not accepting patients for this trial.
For more information, please contact Sheri Krams, PhD, 650-498-6246.
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