Mixed chimerism induced tolerance in heart recipients requires donor kidney cotransplantation

混合嵌合体诱导的心脏受体耐受需要供体肾联合移植

• 批准号: 10518435
• 负责人: Joren C Madsen
• 金额: $ 60.89万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10518435
• 关键词: Acute; Allogenic; Allograft Tolerance; Allografting; Award; B-Lymphocytes; Bone Marrow Transplantation; CD19 gene; CD8B1 gene; Cells; Chimerism; Chronic; Clinical Protocols; Dose; Elements; Family suidae; Funding; Goals; Heart; Heart Transplantation; Histocompatibility; Human; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Instruction; Interleukin-2; Interleukin-6; Kidney; Kidney Transplantation; Lead; Life; Liver; Lung; MS4A1 gene; Miniature Swine; Mus; Nature; Organ; Organ Transplantation; Patients; Population; Principal Investigator; Production; Protocols documentation; Regulatory T-Lymphocyte; Resistance; Resources; T-Lymphocyte; Testing; Thymus Gland; Time; Transplant Recipients; Transplantation; Vascular Diseases; base; cell type; clinically relevant; conditioning; exosome; experimental study; heart allograft; in vivo; kidney allograft; lymphoid structures; microvesicles; nonhuman primate; novel; pandemic disease; response; thymus transplantation

The Project Summary / Abstract is unchanged from original U01AI131470 application: Tolerance of kidney allografts has been achieved in non-human primates (NHPs) and in humans using a combination of nonmyeloablative conditioning and donor bone marrow transplantation (DMBT) that results in transient donor chimerism. However, similar conditioning failed to induce tolerance in heart recipients despite comparable levels of chimerism. The reasons for this organ-specific difference are not clear. However, it is clear that all transplanted organs are not created equally. Not only does the strength of the immune response to a particular organ vary with the organ transplanted but the nature of response itself, rejection versus tolerance, varies from organ to organ. It is well known that some organs, such as kidney and liver, are tolerance-prone while others, such as heart and lung, are tolerance-resistant. In earlier studies using miniature swine, we took advantage of the tolerogenicity of kidney allografts and by cotransplanting donor kidneys with heart allografts, achieved long-term stable tolerance of heart allografts which, if transplanted alone, would have rejected acutely. We have now extended those findings to NHPs by combining donor kidney cotransplantation with a mixed chimerism protocol that induces transient donor chimerism. This protocol is the first to achieve long-term tolerance of MHC mismatched heart allografts in NHPs. Importantly, every recipient that successfully completed its protocol achieved indefinite allograft survival and did so without evidence of cardiac allograft vasculopathy (CAV). Kidney-induced cardiac allograft tolerance (KICAT) is made even more compelling by its consistency across 1) different species (mouse, swine, NHP), 2) different histocompatibility barriers, and 3) different tolerance protocols. These findings suggest that immune mechanisms exist which are capable of inducing tolerance to any organ. Elucidating those mechanisms would lead to strategies that extend tolerance to all allograft recipients. To achieve that goal we propose to 1) investigate novel mechanisms that may explain the tolerogenicity of kidney allografts, 2) evaluate unique regulatory mechanisms the may facilitate KICAT, and 3) test alternative strategies that obviate the need for donor kidney cotransplantation in achieving heart allograft tolerance. Our specific aims are 1) to determine if MHC crossdressing via donor microvesicles (exosomes) or Treg-rich organized lymphoid structures (TOLs) underlie the fundamental differences observed in host alloresponses to kidney allografts, 2) to evaluate the contribution of Tr1 cells and a novel CD8+CD20+ B cell to kidney-induced cardiac allograft tolerance, and 3) to determine if combined low dose IL-2/anti-IL-6R therapy or donor thymus cotransplantation will successfully substitute for donor kidney transplantation and achieve tolerance in recipients of isolated heart allografts. RELEVANCE (See instructions): The

项目摘要/摘要与原U01AI131470申请相同：

项目成果

Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach.

• DOI: 10.1016/j.humimm.2017.11.008
• 发表时间: 2018-05
• 期刊: Human immunology
• 影响因子: 2.7
• 作者: Sasaki H;Oura T;Spitzer TR;Chen YB;Madsen JC;Allan J;Sachs DH;Cosimi AB;Kawai T
• 通讯作者: Kawai T

Kidney-induced systemic tolerance of heart allografts in mice.

小鼠心脏同种异体移植物的肾脏诱导的系统耐受性。

• DOI: 10.1172/jci.insight.139331
• 发表时间: 2020
• 期刊: JCI insight
• 影响因子: 8
• 作者: Yang,Chao;Ge,Jifu;Rosales,Ivy;Yuan,Qing;Szuter,Edward;Acheampong,Ellen;Russell,PaulS;Madsen,JorenC;Colvin,RobertB;Alessandrini,Alessandro
• 通讯作者: Alessandrini,Alessandro

RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression.

非人灵长类同种异体肾移植物的 RNA 表达谱鉴定了 NK 和内皮基因表达的变化。

• DOI: 10.1111/ajt.14639
• 发表时间: 2018
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Smith,RN;Adam,BA;Rosales,IA;Matsunami,M;Oura,T;Cosimi,AB;Kawai,T;Mengel,M;Colvin,RB
• 通讯作者: Colvin,RB

Targeting IL-6 to prevent cardiac allograft rejection.

靶向IL-6以防止心脏同种异体移植排斥。

• DOI: 10.1111/ajt.17206
• 发表时间: 2022-12
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

Ontak-like human IL-2 fusion toxin.

Ontak样人IL-2融合毒素。

• DOI: 10.1016/j.jim.2017.05.008
• 发表时间: 2017-09
• 期刊: Journal of immunological methods
• 影响因子: 2.2
• 作者: Wang Z;Zheng Q;Zhang H;Bronson RT;Madsen JC;Sachs DH;Huang CA;Wang Z
• 通讯作者: Wang Z