Novel indication for myeloid progenitor use: Induction of tolerance

描述（由申请人提供）：在心肺器官移植中，最先进的技术导致10年实体器官移植损失高达80%，并且通常不可能再次移植。供体特异性免疫耐受（DSIT）的建立，即受者在没有免疫抑制的情况下接受移植，同时保留抵抗感染的能力，将减少移植物的损失。唯一确定的诱导强耐受性的方法涉及造血细胞移植（HCT），通常以骨髓移植（BMT）的形式。虽然长期以来被实验认为是诱导DSIT的一种手段，但由于相关的并发症，临床翻译一直受到限制。一个主要的问题是为接受血细胞移植做准备所需的治疗。白细胞计数急剧下降，导致中性粒细胞减少和对感染的易感性增加。为了减少HCT受者中性粒细胞减少相关的感染，可以与HCT一起注射无关的髓系祖细胞（MP）。该疗法在实验室环境中可有效减少细菌和真菌感染造成的死亡，Cellerant Therapeutics (CLT-008) MP公司开发的一种临床MP产品的人体试验正在进行中。我们发现，在这些情况下注射MP会导致MP特异性耐受，即使在第一个月后可能只有非常低水平的MP植入。重要的是，MP来自B10；不能产生功能性B、T或NK细胞的B6-Rag2-/- il2rg -/-小鼠诱导了耐受性，并清楚地表明在这些条件下器官移植匹配的淋巴细胞不是必需的。独特的是，MP细胞在我们的实验模型系统中诱导抗原特异性耐受性，临床可用，并且在当前的临床试验中几乎没有副作用。MP是一种理想的、创新的耐受性诱导方法，优于旨在实现高水平供体嵌合的努力。

DESCRIPTION (provided by applicant): State of the art techniques result in 10-year solid organ graft loss of up to 80% in cardiopulmonary organ transplantation, and re-transplantation is often not possible. Establishment of donor-specific immunological tolerance (DSIT), a condition in which a recipient accepts a transplant without immunosuppression, while retaining the ability to fight infections, would reduce graft loss. The only identified method of inducing robust tolerance involves Hematopoietic Cell Transplantation (HCT), usually in the form of bone marrow transplantation (BMT). Though long recognized experimentally as a means of inducing DSIT, clinical translation has been limited due to the associated complications. A major problem has been the treatment necessary to prepare a recipient for a blood cell transplant. White blood cell counts fall precipitously, resulting in neutropenia and increased susceptibility to infections To reduce infections associated with neutropenia in HCT recipients, unrelated myeloid progenitors (MP) can be injected together with the HCT. This therapy is effective in the laboratory setting in reducing deaths caused by bacterial and fungal infections, and several trials testing a clinical MP product developed by Cellerant Therapeutics (CLT-008) MP in humans are ongoing. We have discovered that injection of MP under these conditions results in MP-specific tolerance, even though there may be only very low-level MP engraftment after the first month. Important, MP from B10;B6-Rag2-/-Il2rg- /- mice, which are incapable of producing functional B, T or NK cells, induce tolerance and clearly show that organ graft-matched lymphoid cells are not essential under these conditions. Uniquely, MP cells induce antigen-specific tolerance in our experimental model system, are clinically available, and have been associated with minimal to no side effects in current clinical trials. MP constitute an ideal and innovative approach in tolerance induction protocols, preferred over efforts aimed at achieving high level donor chimerism. The proposed research in phase I will focus on (Aim 1) testing whether MP can prevent specific lung transplant rejection symptoms, important because lung transplants may be a good patient population for initial trials and (Aim 2) on testing the degree of mismatch allowed between MP and organ graft, as this will affect the production of clinical grade MP for clinical tolerance trils. The design of these trials using a Cellerant produced clinical MP product would be the next stage following this STTR project.