Brenda Velasco

All Publications

• Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning. Cell reports Chang, C. A., Bhagchandani, P., Poyser, J., Velasco, B. J., Zhao, W., Kwon, H., Meyer, E., Shizuru, J. A., Kim, S. K. 2022; 41 (6): 111615

  Abstract

  Mixed hematopoietic chimerism can promote immune tolerance of donor-matched transplanted tissues, like pancreatic islets. However, adoption of this strategy is limited by the toxicity of standard treatments that enable donor hematopoietic cell engraftment. Here, we address these concerns with a non-myeloablative conditioning regimen that enables hematopoietic chimerism and allograft tolerance across fully mismatched major histocompatibility complex (MHC) barriers. Treatment with an alphaCD117 antibody, targeting c-Kit, administered with Tcell-depleting antibodies and low-dose radiation permits durable multi-lineage chimerism in immunocompetent mice following hematopoietic cell transplant. In diabetic mice, co-transplantation of donor-matched islets and hematopoietic cells durably corrects diabetes without chronic immunosuppression and no appreciable evidence of graft-versus-host disease (GVHD). Donor-derived thymic antigen-presenting cells and host-derived peripheral regulatory Tcells are likely mediators of allotolerance. These findings provide the foundation for safer bone marrow conditioning and cell transplantation regimens to establish hematopoietic chimerism and isletallograft tolerance.

  View details for DOI 10.1016/j.celrep.2022.111615

  View details for PubMedID 36351397

• JSP191 As a Single-Agent Conditioning Regimen Results in Successful Engraftment, Donor Myeloid Chimerism, and Production of Donor Derived Naive Lymphocytes in Patients with Severe Combined Immunodeficiency (SCID) Agarwa, R., Dvorak, C. C., Prockop, S., Kwon, H., Long-Boyle, J. R., Le, A., Brown, J. W., Merkel, E., Truong, K., Velasco, B., Arulprakasam, K., Harada, N., Dougall, K. A., Prohaska, S. S., Pang, W. W., Heller, K. N., Weissman, I. L., Cowan, M. J., Logan, A. C., O'Reilly, R. J., Parkman, R., Weinberg, K. I., Roncarolo, M., Shizuru, J. A. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-153074

  View details for Web of Science ID 000736398802095

• 5-Azacytidine depletes hematopoietic stem cells and synergizes with an anti-CD117 antibody to augment donor engraftment in immunocompetent mice. Blood advances Bankova, A. K., Pang, W., Velasco, B. J., Long-Boyle, J. R., Shizuru, J. A. 2021

  Abstract

  Depletion of hematopoietic stem cells (HSC) is used therapeutically in many malignant and non-malignant blood disorders in the setting of a hematopoietic cell transplantation (HCT) to eradicate diseased HSC allowing donor HSC to engraft. Current treatments to achieve HSC elimination rely on modalities that cause DNA strand breakage (i.e., alkylators, radiation) resulting in multiple short-term and long-term toxicities, and sometimes even death. These risks have severely limited HCT utilization to patients with few to no co-morbidities, and excluded many others with diseases curable by HCT. 5-Azacytidine (AZA) is a widely used hypomethylating agent that is thought to preferentially target leukemic cells in myeloid malignancies. Here, we reveal a previously unknown effect of AZA on HSC. We show that AZA induces early HSC proliferation in vivo and exerts a direct cytotoxic effect on proliferating HSC in vitro. When used to pretreat recipient mice for transplant, AZA permitted low level donor HSC engraftment. Moreover, by combining AZA with a monoclonal antibody (mAb), targeting CD117 (c-Kit), a molecule expressed on HSC, more robust HSC-depletion and substantially higher levels of multilineage donor cell engraftment was achieved in immunocompetent mice. The enhanced effectiveness of this combined regimen correlated with increased apoptotic cell death in HSPC. Together, these findings highlight a previously unknown therapeutic mechanism for AZA which may broaden its utilization in clinical practice. Moreover, the synergy we show between AZA and anti-CD117 mAb is a novel strategy to eradicate abnormal HSC which can be rapidly tested in the clinical setting.

  View details for DOI 10.1182/bloodadvances.2020003841

  View details for PubMedID 34448832

• Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance. Cell stem cell George, B. M., Kao, K. S., Kwon, H., Velasco, B. J., Poyser, J., Chen, A., Le, A. C., Chhabra, A., Burnett, C. E., Cajuste, D., Hoover, M., Loh, K. M., Shizuru, J. A., Weissman, I. L. 2019

  Abstract

  Hematopoietic cell transplantation can correct hematological and immunological disorders by replacing a diseased blood system with a healthy one, but this currently requires depleting a patient's existing hematopoietic system with toxic and non-specific chemotherapy, radiation, or both. Here we report an antibody-based conditioning protocol with reduced toxicity and enhanced specificity for robust hematopoietic stem cell (HSC) transplantation and engraftment in recipient mice. Host pre-treatment with six monoclonal antibodies targeting CD47, Tcells, NK cells, and HSCs followed by donor HSC transplantation enabled stable hematopoietic system reconstitution in recipients with mismatches at half (haploidentical) or all major histocompatibility complex (MHC) genes. This approach allowed tolerance to heart tissue from HSC donor strains in haploidentical recipients, showing potential applications for solid organ transplantation without immune suppression. Fully mismatched chimeric mice developed antibody responses to nominal antigens, showing preserved functional immunity. These findings suggest approaches for transplanting immunologically mismatched HSCs and solid organs with limited toxicity.

  View details for DOI 10.1016/j.stem.2019.05.018

  View details for PubMedID 31204177