PMID- 31258526 OWN - NLM STAT- MEDLINE DCOM- 20201109 LR - 20201109 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients. PG - 1244 LID - 10.3389/fimmu.2019.01244 [doi] LID - 1244 AB - Adipose mesenchymal stem cells (ASC) are considered minimally immunogenic. This is due to the low expression of human leukocyte antigens I (HLA-I), lack of HLA-II expression and low expression of co-stimulatory molecules such as CD40 and CD80. The low rate of observed immunological rejection as well as the immunomodulatory qualities, position ASC as a promising cell-based therapy for the treatment of a variety of inflammatory indications. Yet, few studies have addressed relevant aspects of immunogenicity such as ASC donor-to-patient HLA histocompatibility or assessment of immune response triggered by ASC administration, particularly in the cases of presensitization. The present study aims to assess allo-immune responses in a cohort of Crohn's disease patients administered with allogeneic ASC (darvadstrocel formerly Cx601) for the treatment of complex perianal fistulas. We identified donor-specific antibodies (DSA) generation in a proportion of patients and observed that patients showing preexisting immunity were prone to generating DSA after allogeneic therapy. Noteworthy, naive patients generating DSA at week 12 (W12) showed a significant reduction in DSA titer at week 52 (W52), whereas DSA titer was reduced in pre-sensitized patients only with no specificities against the donor administered. Remarkably, we did not observe any correlation of DSA generation with ASC therapeutic efficacy. In vitro complement-dependent cytotoxicity (CDC) studies have revealed limited cytotoxic levels based upon HLA-I expression and binding capacity even in pro-inflammatory conditions. We sought to identify CDC coping mechanisms contributing to the limited cytotoxic killing observed in ASC in vitro. We found that ASC express membrane-bound complement regulatory proteins (mCRPs) CD55, CD46, and CD59 at basal levels, with CD46 more actively expressed in pro-inflammatory conditions. We demonstrated that CD46 is a main driver of CDC signaling; its depletion significantly enhances sensitivity of ASC to CDC. In summary, despite relatively high clearance, DSA generation may represent a major challenge for allogeneic cell therapy management. Sensitization may be a significant concern when evaluating re-treatment or multi-donor trials. It is still unknown whether DSA generation could potentially be the consequence of donor-to-patient interaction and, therefore, subsequently link to efficacy or biological activity. Lastly, we propose that CDC modulators such as CD46 could be used to ultimately link CDC specificity with allogeneic cell therapy efficacy. FAU - Avivar-Valderas, Alvaro AU - Avivar-Valderas A AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Martin-Martin, Cristina AU - Martin-Martin C AD - Department of Immunology, University Hospital Ramon y Cajal, Madrid, Spain. FAU - Ramirez, Cristina AU - Ramirez C AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Del Rio, Borja AU - Del Rio B AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Menta, Ramon AU - Menta R AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Mancheno-Corvo, Pablo AU - Mancheno-Corvo P AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Ortiz-Virumbrales, Maitane AU - Ortiz-Virumbrales M AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Herrero-Mendez, Angel AU - Herrero-Mendez A AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Panes, Julian AU - Panes J AD - Department of Gastroenterology, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain. FAU - Garcia-Olmo, Damian AU - Garcia-Olmo D AD - Department of Surgery, Hospital U. Fundacion Jimenez Diaz, Madrid, Spain. FAU - Castaner, Jose Luis AU - Castaner JL AD - Department of Immunology, University Hospital Ramon y Cajal, Madrid, Spain. FAU - Palacios, Itziar AU - Palacios I AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Lombardo, Eleuterio AU - Lombardo E AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. FAU - Dalemans, Wilfried AU - Dalemans W AD - TiGenix NV, Leuven, Belgium. FAU - DelaRosa, Olga AU - DelaRosa O AD - Takeda Madrid, Cell Therapy Technology Center-Cell Therapies, Madrid, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190614 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (HLA Antigens) RN - 0 (Isoantigens) RN - 0 (Membrane Cofactor Protein) SB - IM MH - Adipose Tissue/cytology MH - Adult MH - Animals MH - Cells, Cultured MH - Cohort Studies MH - Complement Activation MH - Crohn Disease/complications/*therapy MH - Female MH - Fistula/complications/*therapy MH - Graft Rejection/etiology/*immunology MH - HLA Antigens/immunology MH - Humans MH - Immunity, Humoral MH - Immunization MH - Isoantigens/immunology MH - Male MH - Membrane Cofactor Protein/metabolism MH - *Mesenchymal Stem Cell Transplantation MH - Mesenchymal Stem Cells/cytology MH - Perianal Glands/*pathology/surgery MH - Postoperative Complications/*immunology MH - Transplantation, Homologous PMC - PMC6587893 OTO - NOTNLM OT - ASC OT - CD46 OT - HLA class 1 OT - allo-sensitization OT - allogeneic OT - cell therapy and immunotherapy OT - complement dependent cytotoxicity (CDC) OT - crispr gene editing EDAT- 2019/07/02 06:00 MHDA- 2020/11/11 06:00 PMCR- 2019/01/01 CRDT- 2019/07/02 06:00 PHST- 2019/03/19 00:00 [received] PHST- 2019/05/16 00:00 [accepted] PHST- 2019/07/02 06:00 [entrez] PHST- 2019/07/02 06:00 [pubmed] PHST- 2020/11/11 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.01244 [doi] PST - epublish SO - Front Immunol. 2019 Jun 14;10:1244. doi: 10.3389/fimmu.2019.01244. eCollection 2019.