Research in the Nelson laboratory focuses on the immune system’s response to organ transplants and blood transfusions. Dr. Nelson’s lab partners with clinician scientists in identifying biomarkers (substances that can be detected in the blood) that can be used to measure the patient’s risk of having a reaction. The lab translates results obtained from research into tests that can be used in clinical management.
Areas of Study
Dr. Nelson’s Background
The Nelson laboratory studies the response of CD8 T lymphocytes to donor human leukocyte antigens (HLA) after transplantation, identification of the elements generated from clinical laboratory assays that make up the profile of a recipient of a successful solid-organ transplant, and immunomodulation following transfusion.
Areas of Study
CD8 T lymphocytes and Transplantation
T lymphocytes of the lineage identified by the CD8 marker have receptors for class I MHC plus peptide. Their role in response to transplanted organs has historically been thought to be limited to mediators of acute rejection via direct cytotoxicity or interactions between receptors and proteins of the tumor necrosis factor (TNF) family. However, the larger group of CD8 T cells includes cells with the capacity to down-regulate the activity of other T cells either via direct contact, via secreted cytokines, or via action on antigen-presenting cells. These CD8 cells with regulatory capacity can be differentiated by the expression of the cytokine IL-10 as opposed to the expression of granzymes or other cytotoxic mediators. Dr. Nelson’s lab has been analyzing peripheral blood samples taken prior to and following transplantation for CD8 cells that proliferate in response to re-exposure to donor HLA antigens ex vivo. The cytoplasm of proliferating cells has been stained to identify expression of IL-10, IFN-gamma or granzymes to identify cells with regulatory or cytotoxic phenotypes. The lab’s hypothesis is that increases in cells with regulatory capacity after re-stimulation with donor tissue is a marker for a reduced risk of rejection.
The rapid translation of research techniques into clinically applicable assays and methods is enabling the lab to individualize the management of patients after transplantation. The assays employed allow snapshots of the immune response to HLA and tissue–specific antigens of the transplant donor. Data from these snapshots are then assembled to make up a profile that can be correlated with real-time data on the status of the transplanted organ. Elements associated with stable function or pending rejection will in the future be used to guide selection of immunosuppressive strategies or monitor tolerance-induction protocols.
Identification of Antibodies to HLA in Solid Organ Transplantation
Recent advances in microparticle-based flow cytometry assays now allow for the detection and identification of antibodies against single HLA molecules. Dr. Nelson’s lab is participating in research to identify the clinical correlates of different titers of antibodies detected by these assays: immune memory or active response. Data from these assays may form the basis for allocation of organs from deceased donors. The lab is partnering with other HLA laboratories in piloting this change. These new tools are not completely understood – there is ongoing research to identify artifacts and holes created by the nature of the recombinant molecules.
Data from these assays are also among the elements of the profile of an organ recipient. It was previously assumed that any donor-specific antibody generated after transplant was a predictor of rejection. Another focus of the lab’s studies is the hypothesis that antibodies with low titer or directed against antigens with a lower copy number may give survival signals and not mediate rejection.
Identification of Cytokine Profiles of Lymphocytes Responding to Donor Tissue
Lymphocytes responding to transplanted organs include the CD8 T lymphocytes described above, as well as CD4 T lymphocytes and natural killer t-cells (NKT) cells. Changes in these populations after transplant are elements of the organ recipient profile. NKT studies are performed in Dr. Warner’s laboratory.
Impact of Transfusion Component Processing
Filtration of transfusion components has been advanced as a solution to post-transfusion immunomodulation. However, most of the studies on allosensitization have used immunosuppressed subjects and studies on immunosuppression have used clinical outcomes as the endpoints. Dr. Nelson’s lab’s studies are targeting cardiac surgery patients (non-immunosuppressed) in collaboration with Dr. Gabriel Aldea at the University of Washington. The lab is measuring antibodies to HLA with the microparticle assays described above. These assays have the advantage of identifying changes in antibodies in patients previously allosensitized. To study immunosuppression, Dr. Paul Warner is analyzing the effects of transfusion on NKT cells and Yvette Latchman is studying CD4 T regulatory cells.
Transfusion-Associated Acute Lung Injury (TRALI)
In collaboration with Dr. Theresa Nester, the Blood Center’s Associate Medical Director, and Dr. Terry Gernsheimer, the Blood Center’s Director of Medical Education, Dr. Nelson’s lab is measuring antibodies to HLA antigens in transfusion components as well as in recipients with clinical symptoms meeting the criteria for TRALI.
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