Project description:Background: Primary immunodeficiency patients are ineligible for lung transplant (LTX) due to futility and bone marrow transplant (BMT) for lung failure. We hypothesized that using marrow extracted from the vertebral bodies (VB) of a deceased lung donor with partial HLA-match would be able to establish persistent hematopoiesis and generate immunity and tolerance. Methods: A teenager with severe combined immunodeficiency in lung failure due to recurrent pneumonias underwent LTX in 2016 from a 1/8 HLA allele-matched unrelated donor followed by reduced intensity conditioning and infusion of T cell/B cell-depleted cryopreserved VB marrow 4 months later. Results: Immune competence and donor-derived thymopoiesis were evident by six months post-BMT, while immunosuppression was withdrawn at 16-month post-BMT. Donor T cell (>95%) and myeloid chimerism (7-10%) have persisted for over nine years. At two years post-BMT, circulating donor-derived T cells were hyporesponsive to host dendritic cells in vitro. T-cell receptor clonotyping revealed the disappearance of host-reactive clones identifiable in the marrow graft, while circulating donor T cells exhibited downmodulation of signaling pathways for cytotoxicity/rejection, paired with upregulated immunomodulatory pathways, suggesting active suppression. In parallel, circulating predominantly host monocytes upregulated signaling pathways compared to their donor-derived counterparts, indicating active interactions between post-thymic donor T cells and host monocytes. Conclusion: In summary, durable hematopoietic engraftment and protective immunity were demonstrable for the first time in a patient receiving deceased donor vertebral bone marrow graft. Moreover, tolerance exceeding 8-years without immunosuppression was attainable.
Project description:RATIONALE: Giving high doses of chemotherapy drugs, such as busulfan and cyclophosphamide, before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient’s immune system from rejecting the donor’s stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient’s bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body’s normal cells. Giving cyclosporine, methylprednisolone, and methotrexate after transplant may stop this from happening.
PURPOSE: This clinical trial studies high-dose busulfan and high-dose cyclophosphamide followed by donor bone marrow transplant in treating patients with leukemia, myelodysplastic syndrome, multiple myeloma, or recurrent Hodgkin or Non-Hodgkin lymphoma.
Project description:This phase II trial studies how well giving fludarabine phosphate, cyclophosphamide, tacrolimus, mycophenolate mofetil and total-body irradiation together with a donor bone marrow transplant works in treating patients with high-risk hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells by stopping them from dividing or killing them. Giving cyclophosphamide after transplant may also stop the patient’s immune system from rejecting the donor’s bone marrow stem cells. The donated stem cells may replace the patient’s immune system cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body’s normal cells. Giving tacrolimus and mycophenolate mofetil after the transplant may stop this from happening
Project description:This pilot clinical trial studies low-dose total body irradiation and donor peripheral blood stem cell transplant followed by donor lymphocyte infusion in treatment patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, or multiple myeloma. Giving total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When healthy stem cells from a donor are infused into the patient they may help the patient’s bone marrow make stem cells, red blood cells, white blood cells, and platelets. Once the donated stem cells begin working, the patient’s immune system may see the remaining cancer cells as not belonging in the patient’s body and destroy them. Giving an infusion of the donor’s white blood cells (donor lymphocyte infusion) may boost this effect.
Project description:Human fetal and adult hematopoietic stem cells (HSC) were obtained from fetal liver, fetal bone marrow (BM), and adult BM. These were injected into human fetal thymic implants in SCID-hu Thy/Liv mice (4-6 separate mice per HSC donor) and allowed to mature into single positive CD4+ (SP4) thymocytes over the course of 7-8 weeks. SP4 thymocytes from injected stem cells were subsequently sort-purified from thymic implants and gene expression was performed. HSC from fetal (age 18-22 gestational weeks) and adult (age: 19-43 year old) HLA-A2+ donors were obtained from different tissues. After injection into human fetal thymic implants (SCID-hu Thy/Liv HLA-A2-) the cells were allowed to mature into thymocytes and sorted on the basis of HLA-A2+ expression and CD3+CD4+ (SP4) expression. 3 separate thymic implants were analyzed for each group.
Project description:Sorted cells from bone marrow and rectal mucosa of SIV-infected rhesus macaques were analyzed for expression of factors associated with plasma cell recruitment, adhesion, or maintenance mRNA expression anaylsis was performed on 16 CD2-CD19-CD20-HLA-DR+ and 16 CD2-CD19-CD20-HLA-DR- bone marrow cells, and 7 CD2-CD19-CD20-HLA-DR+ and 3 CD2-CD19-CD20-HLA-DR- rectal cells using a custom CodeSet produced by NanoString Technologies containing 44 niche factor genes of interst, 12 cell-type specific genes, and 9 reference genes identified in Genevestigator.