Short-course rapamycin treatment enables engraftment of immunogenic gene-engineered bone marrow under low-dose irradiation to permit long-term immunological tolerance
| Autor: | Kunal H. Bhatt, Raymond J. Steptoe, Ryan Galea, James W. Wells, Rajeev Rudraraju, Jeremy F. Brooks, Ji-Won Jung |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Transplantation Conditioning Medicine (miscellaneous) Bone Marrow Cells Biology Biochemistry Genetics and Molecular Biology (miscellaneous) Immune tolerance Mice 03 medical and health sciences Gene therapy 0302 clinical medicine medicine Animals Humans Cytotoxic T cell Progenitor cell Cell Engineering Bone Marrow Transplantation Sirolimus Peripheral tolerance induction Radiation Research Hematopoietic Stem Cell Transplantation Dendritic Cells Genetic Therapy Cell Biology Total body irradiation Hematopoietic Stem Cells 3. Good health Tolerance induction 030104 developmental biology medicine.anatomical_structure Bone marrow transplant Immunology Molecular Medicine Bone marrow Stem cell T-Lymphocytes Cytotoxic 030215 immunology |
| Zdroj: | Stem Cell Research & Therapy |
| ISSN: | 1757-6512 |
| DOI: | 10.1186/s13287-017-0508-3 |
| Popis: | Background Application of genetically modified hematopoietic stem cells is increasingly mooted as a clinically relevant approach to protein replacement therapy, immune tolerance induction or conditions where both outcomes may be helpful. Hematopoietic stem and progenitor cell (HSPC)-mediated gene therapy often requires highly toxic pretransfer recipient conditioning to provide a ‘niche’ so that transferred HSPCs can engraft effectively and to prevent immune rejection of neoantigen-expressing engineered HSPCs. For widespread clinical application, reducing conditioning toxicity is an important requirement, but reduced conditioning can render neoantigen-expressing bone marrow (BM) and HSC susceptible to immune rejection if immunity is retained. Methods BM or HSPC-expressing OVA ubiquitously (actin.OVA) or targeted to MHC II+ cells was transferred using low-dose (300 cGy) total body irradiation. Recipients were administered rapamycin, cyclosporine or vehicle for 3 weeks commencing at BM transfer. Engraftment was determined using CD45 congenic donors and recipients. Induction of T-cell tolerance was tested by immunising recipients and analysing in-vivo cytotoxic T-lymphocyte (CTL) activity. The effect of rapamycin on transient effector function during tolerance induction was tested using an established model of tolerance induction where antigen is targeted to dendritic cells. Results Immune rejection of neoantigen-expressing BM and HSPCs after low-dose irradiation was prevented by a short course of rapamycin, but not cyclosporine, treatment. Whereas transient T-cell tolerance developed in recipients of OVA-expressing BM administered vehicle, only when engraftment of neoantigen-expressing BM was facilitated with rapamycin treatment did stable, long-lasting T-cell tolerance develop. Rapamycin inhibited transient effector function development during tolerance induction and inhibited development of CTL activity in recipients of OVA-expressing BM. Conclusions Rapamycin acts to suppress acquisition of transient T-cell effector function during peripheral tolerance induction elicited by HSPC-encoded antigen. By facilitating engraftment, short-course rapamycin permits development of long-term stable T-cell tolerance. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0508-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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