TOLerogenic Potential of Hematopoietic Stem and Progenitor Cells and Inflammatory Bowel Disease (TOL-IBD)
Exploring and Exploiting the TOLerogenic Potential of Hematopoietic Stem and Progenitor Cells to Cure Pediatric Inflammatory Bowel Disease
연구 개요
상태
상태
정황
정황
개입 / 치료
개입 / 치료
상세 설명
Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract, with Crohn's Disease (CD) and Ulcerative Colitis (UC) being the main types. The causes of IBD are complex and include immune dysregulation with activation of immune cells, release of inflammatory cytokines, and intestinal tissue damage. Despite significant advances in the treatment of pediatric IBD, a large unmet need for a definitive cure remains, and cell immunotherapy is under investigation. The investigators are specifically interested in refractory IBD, a chronic active condition requiring continuous treatment for symptom relief, with detrimental side effects. Despite the several treatment options currently available, 30% of pediatric IBD patients are refractory, and none of the existing treatments results in complete remission.
Interleukin 10 (IL-10) is an immunoregulatory cytokine associated with IBD pathogenesis and regulating gut homeostasis. Type 1 regulatory T (Tr1) cells produce IL-10 and their function is crucial for suppression of inflammation in IBD. The investigators recently published that antigen (Ag)-specific immune responses in Celiac Disease can be controlled via IL-10-producing Ag-presenting cells engineered to express a gliadin epitope, demonstrating that Ag-presenting cells can be manipulated to promote Tr1 cell differentiation.
Significant advances in the field of hematopoietic stem and progenitor cells (HSPCs) engineering and biology have been achieved. The development of protocols for ex-vivo manipulation and expansion of circulating (c)HSPCs and of mobilization-based chemotherapy-free approaches broadens the applicability of HSPC-based therapies to diseases for which HSPC transplantation is not the standard of care. A recent report showed that Tr1 cells can be promoted by immunogenic HSPC, which present Ags via HLA class II to CD4+ T cells in the bone marrow. This discovery opens new avenues for the development of approaches exploiting the Ag-presenting capacity and the tolerogenic potential of HSPCs to counteract inflammation in target tissues.
Based on these premises, with the final goal of developing a procedure for the induction of IL-10-mediated tolerance to control intestinal inflammation in refractory IBD pediatric patients, the investigators will:
- Investigate the type and frequency of inflammatory and regulatory immune cells, including IL-10-related regulatory cells, infiltrating the gut mucosa of IBD and non-IBD control patients. Results will indicate whether enforcement of the regulatory arm would benefit IBD patients. To this aim, it is necessary to collect and analyze intestinal tissue fragments from IBD and non-IBD control patients.
- Investigate the type and frequency of immune cells, including IL-10-related regulatory cells, circulating in the peripheral blood of IBD patients and non-IBD control patients. Results will indicate whether enforcement of the regulatory arm would benefit IBD patients. To this aim it is necessary to collect PB from IBD and non-IBD control patients.
- Characterize the presence, phenotype, and expansion potential of CD34+ HSPCs circulating in the peripheral blood of IBD patients. To this end, the investigators will collect peripheral blood from IBD patients, and i) assess the frequency, composition, and Ag-presenting potential of and ii) apply ex-vivo expansion and engineering protocols to CD34+ HSPC circulating in the peripheral blood of IBD patients. These results will be pivotal for assessing the feasibility of HSPC-based approaches to restore homeostasis in the intestinal tissue in refractory pediatric IBD.
- Evaluate the response to commensal-derived Ags (e.g., Bacteroides-derived peptides) of CD4+ T lymphocytes circulating by collecting the peripheral blood of IBD patients, non-IBD control patients, and healthy subjects as control. These results will indicate which Ag could be used for HSPC engineering and for inducing IL-10-producing regulatory T cells.
- Assess the ability of human HSPCs to promote Ag-specific Tr1 cells in vitro. To this end, selected IBD patients known to be responders commensal -derived Ags (as above) and peripheral blood will be collected at 1 year (6-18 months) follow-up. The investigators will engineer circulating HSPCs ex-vivo expanded from the peripheral blood of selected IBD patients and test for their ability to promote Ag-specific Tr1 cell upon in vitro culture with autologous CD4+ T cells.
연구 유형
연구 유형
등록 (추정된)
등록
연락처 및 위치
연구 연락처
연구 연락처
- 이름: Silvia Gregori, PhD
- 전화번호: +390226434894
- 이메일: gregori.silvia@hsr.it
연구 연락처 백업
- 이름: Laura Passerini, PhD
- 전화번호: +390226439303
- 이메일: passerini.laura@hsr.it
연구 장소
-
-
-
Milan, 이탈리아, 20132
- Pediatric Immunohematology Unit, IRCCS Ospedale San Raffaele
-
연락하다:
- Federica Barzaghi, MD
- 전화번호: +390226432979
- 이메일: barzaghi.federica@hsr.it
-
Rome, 이탈리아, 00189
- UOC Pediatria, Azienda Ospedaliero-Universitaria Sant'Andrea
-
연락하다:
- Giovanni Di Nardo, MD
- 전화번호: +390633775971
- 이메일: giovanni.dinardo@uniroma1.it
-
-
참여기준
자격 기준
자격 기준
공부할 수 있는 나이
- 어린이
- 성인
건강한 자원 봉사자를 받아들입니다
샘플링 방법
연구 인구
Eligible participants will be consecutively enrolled as they present to the clinical centers until the planned sample size is achieved.
The Study will include pediatric subjects, both males and females belonging to the following study populations:
- IBD patients: pediatric patients with chronic intestinal inflammation (i.e., inflammatory bowel disease (IBD), including Crohn Disease, Ulcerative Colitis) at diagnosis or follow-up (including responders to standard of care and refractory to treatment);
- Non-IBD patients: patients with rectal bleeding with a negative colonoscopy and the exclusion of any inflammatory disorders of the gastrointestinal tract;
- Healthy controls: healthy volunteers participating in the TIGET09 study protocol ("Collection of biological samples for the study of blood cells and their microenvironment, and for the development of novel therapeutic approaches for genetic diseases and cancer."), as control population.
설명
Inclusion Criteria:
For all groups:
- Written informed consent from parent(s)/legal guardian(s);
- Sex: Males and Females;
- Age: ≥2 years and <18 years.
For study group 1:
- Subjects with suspected or confirmed IBD diagnosis.
For study group 2:
- Subjects with rectal bleeding w/o inflammatory disorders of the gastrointestinal tract.
For study group 3:
- Written consent for participation to TIGET09 study protocol;
- healthy subjects, without known immunodeficiencies, autoimmune, inflammatory or genetic diseases, undergoing genetic, hematological, hematochemical, or HLA compatibility screenings and participating in the TIGET09 study protocol (Title: "Collection of biological samples for the study of blood cells and their microenvironment, and for the development of novel therapeutic approaches for genetic diseases and cancer").
Exclusion Criteria:
For all groups:
- Refusal or inability of the parent(s) or legal guardian(s) to provide written informed consent;
- Age: <2 years and ≥18 years;
- Presence of any medical, psychiatric, or clinical condition that, in the opinion of the clinician, may interfere with participation in the study or interpretation of the study results;
For study group 1:
- patients without IBD diagnosis or suspect;
For study group 2:
- Subjects without rectal bleeding or with known inflammatory/autoimmune disorders of the gastrointestinal tract.
For all groups:
- Refusal or inability of the parent(s) or legal guardian(s) to provide written informed consent;
- Age: <2 years and ≥18 years;
- Presence of any medical, psychiatric, or clinical condition that, in the opinion of the clinician, may interfere with participation in the study or interpretation of the study results;
For study group 1:
- patients without IBD diagnosis or suspect;
For study group 2:
- Subjects without rectal bleeding or with known inflammatory/autoimmune disorders of the gastrointestinal tract.
For study group 3:
- Lack of written consent for participation to TIGET09 study protocol;
- patients belonging to study groups 1 and 2; patients with immunodeficiencies, autoimmune, inflammatory or genetic diseases;
- subjects with signs of systemic inflammation.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
그룹/코호트 수
코호트 및 개입
그룹/코호트그룹/코호트 |
개입 / 치료개입 / 치료 |
|---|---|
|
Study Group 1
IBD patients: pediatric patients with chronic intestinal inflammation (i.e., inflammatory bowel disease (IBD), including Crohn Disease, Ulcerative Colitis) at diagnosis or follow-up (including responders to standard of care and refractory to treatment)
|
An additional volume of peripheral blood (3-10 ml) will be obtained in concomitance with clinically indicated procedures
A small fragment (1-5 mm) of intestinal tissue - residual or leftover material -will be obtained from patients undergoing diagnostic or follow-up endoscopy
|
|
Study Group 2
Non-IBD patients: patients with rectal bleeding with a negative colonoscopy and the exclusion of any inflammatory disorders of the gastrointestinal tract
|
An additional volume of peripheral blood (3-10 ml) will be obtained in concomitance with clinically indicated procedures
A small fragment (1-5 mm) of intestinal tissue - residual or leftover material -will be obtained from patients undergoing diagnostic or follow-up endoscopy
|
|
Study Group 3
Healthy volunteers (controls)
|
Peripheral blood samples from healthy subjects, leftover from TIGET09 protocol analysis will be collected
|
연구는 무엇을 측정합니까?
주요 결과 측정
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
To characterize pediatric IBD patients' peripheral blood and intestinal mucosa immune cell composition
기간: Baseline timepoint
|
Frequency (%) of predefined regulatory and inflammatory immune-cell subsets in peripheral blood and gut mucosa, including regulatory T cells (FOXP3+ Tregs and IL-10 producing Tr1 cells), T naïve/memory and effector cells, regulatory myeloid cells (DC-10), and inflammatory myeloid cells (cDC1 and cDC2), measured by flow cytometry. The primary objective will be considered met if patients with IBD show a lower frequency of IL-10-producing cells than controls, with the estimated between-group difference supporting a defect in IL-10-producing cell responses. |
Baseline timepoint
|
2차 결과 측정
2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
To explore the ability of HSPCs to induce in vitro the differentiation of Ag-specific Tr1 cells.
기간: Baseline and 1 year follow up
|
Induction of Tr1-like cells following T-cell/HSPC co-culture, assessed by: frequency (%) of cells expressing the Tr1-associated phenotype and expression of Tr1-associated genes. Success criterion (exploratory): Generation of a T-cell population displaying Tr1-associated features. |
Baseline and 1 year follow up
|
공동 작업자 및 조사자
수사관
수사관
- 수석 연구원: Silvia Gregori, PhD, IRCCS Ospedale San Raffaele
- 수석 연구원: Alessandro Aiuti, MD, IRCCS Ospedale San Raffaele
간행물 및 유용한 링크
일반 간행물
- Parigi TL, D'Amico F, Abreu MT, Dignass A, Dotan I, Magro F, Griffiths AM, Jairath V, Iacucci M, Mantzaris GJ, O'Morain C, Reinisch W, Sachar DB, Turner D, Yamamoto T, Rubin DT, Peyrin-Biroulet L, Ghosh S, Danese S. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023 Sep;8(9):853-859. doi: 10.1016/S2468-1253(23)00154-1. Epub 2023 Jul 6.
- Hernandez-Malmierca P, Vonficht D, Schnell A, Uckelmann HJ, Bollhagen A, Mahmoud MAA, Landua SL, van der Salm E, Trautmann CL, Raffel S, Grunschlager F, Lutz R, Ghosh M, Renders S, Correia N, Donato E, Dixon KO, Hirche C, Andresen C, Robens C, Werner PS, Boch T, Eisel D, Osen W, Pilz F, Przybylla A, Klein C, Buchholz F, Milsom MD, Essers MAG, Eichmuller SB, Hofmann WK, Nowak D, Hubschmann D, Hundemer M, Thiede C, Bullinger L, Muller-Tidow C, Armstrong SA, Trumpp A, Kuchroo VK, Haas S. Antigen presentation safeguards the integrity of the hematopoietic stem cell pool. Cell Stem Cell. 2022 May 5;29(5):760-775.e10. doi: 10.1016/j.stem.2022.04.007.
- Omer-Javed A, Pedrazzani G, Albano L, Ghaus S, Latroche C, Manzi M, Ferrari S, Fiumara M, Jacob A, Vavassori V, Nonis A, Canarutto D, Naldini L. Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells. Cell. 2022 Jun 23;185(13):2248-2264.e21. doi: 10.1016/j.cell.2022.04.039. Epub 2022 May 25.
- Capo V, Penna S, Merelli I, Barcella M, Scala S, Basso-Ricci L, Draghici E, Palagano E, Zonari E, Desantis G, Uva P, Cusano R, Sergi Sergi L, Crisafulli L, Moshous D, Stepensky P, Drabko K, Kaya Z, Unal E, Gezdirici A, Menna G, Serafini M, Aiuti A, Locatelli SL, Carlo-Stella C, Schulz AS, Ficara F, Sobacchi C, Gentner B, Villa A. Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis. Haematologica. 2021 Jan 1;106(1):74-86. doi: 10.3324/haematol.2019.238261.
- Passeri L, Andolfi G, Bassi V, Russo F, Giacomini G, Laudisa C, Marrocco I, Cesana L, Di Stefano M, Fanti L, Sgaramella P, Vitale S, Ziparo C, Auricchio R, Barera G, Di Nardo G, Troncone R, Gianfrani C, Annoni A, Passerini L, Gregori S. Tolerogenic IL-10-engineered dendritic cell-based therapy to restore antigen-specific tolerance in T cell mediated diseases. J Autoimmun. 2023 Jul;138:103051. doi: 10.1016/j.jaut.2023.103051. Epub 2023 May 22.
- Cook L, Stahl M, Han X, Nazli A, MacDonald KN, Wong MQ, Tsai K, Dizzell S, Jacobson K, Bressler B, Kaushic C, Vallance BA, Steiner TS, Levings MK. Suppressive and Gut-Reparative Functions of Human Type 1 T Regulatory Cells. Gastroenterology. 2019 Dec;157(6):1584-1598. doi: 10.1053/j.gastro.2019.09.002. Epub 2019 Sep 10.
- Krawiec P, Pawlowska-Kamieniak A, Pac-Kozuchowska E. Interleukin 10 and interleukin 10 receptor in paediatric inflammatory bowel disease: from bench to bedside lesson. J Inflamm (Lond). 2021 Mar 10;18(1):13. doi: 10.1186/s12950-021-00279-3.
- Neurath MF, Sands BE, Rieder F. Cellular immunotherapies and immune cell depleting therapies in inflammatory bowel diseases: the next magic bullet? Gut. 2024 Dec 10;74(1):9-14. doi: 10.1136/gutjnl-2024-332919.
연구 기록 날짜
연구 주요 날짜
연구 시작 (추정된)
연구 시작
기본 완료 (추정된)
기본 완료
연구 완료 (추정된)
연구 완료
연구 등록 날짜
최초 제출
최초 제출
QC 기준을 충족하는 최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
처음 게시됨
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
마지막 업데이트 게시됨
QC 기준을 충족하는 마지막 업데이트 제출
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
키워드
기타 연구 ID 번호
기타 연구 ID 번호
- RF-2024-12378919 (기타 보조금/기금 번호: Ministero della Salute - Bando Ricerca finalizzata 2024)
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .