Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.
Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.
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DOI：
10.1126/scitranslmed.3003509
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发表时间：
2012-03-07
影响因子：
17.1
通讯作者：
Ildstad ST
中科院分区：
文献类型：
--
作者：
Leventhal J;Abecassis M;Miller J;Gallon L;Ravindra K;Tollerud DJ;King B;Elliott MJ;Herzig G;Herzig R;Ildstad ST
器官移植维持所需的慢性免疫抑制剂的毒性促使研究人员寻求诱导免疫耐受的方法。我们开发了一种方法，使用富含造血干细胞（HSC）和致耐受性CD 8 +/TCR−移植促进细胞（FC）的生物工程动员细胞产物，结合非清髓性预处理，允许在高度不匹配的相关和无关供体-受体对中植入，持久嵌合和耐受诱导。8例HLA不匹配的肾和FC/HSC移植受者接受了氟达拉滨、200 cGy全身照射和环磷酰胺预处理，随后接受了他克莫司和霉酚酸酯移植后免疫抑制。受试者的年龄范围为29至56岁。HLA匹配范围为5/6相关和1/6无关。中性粒细胞绝对计数在移植后约一周降至最低点，两周后恢复。一个月时的多谱系嵌合体为6%至100%。术后第2天，门诊管理对预处理耐受良好。2例受试者表现出一过性嵌合体，已减少至低剂量他克莫司单药治疗。1例受试者在移植后2个月发生病毒性脓毒症，并发生肾动脉血栓形成。5例受试者具有持久的嵌合体，通过体外增殖试验具有免疫活性和供体特异性耐受性，并在移植后一年成功地摆脱了所有免疫抑制。所有受者均未产生抗供体抗体或表现出移植物植入综合征或移植物抗宿主病。这些结果表明，动员干细胞移植和非清髓性预处理的操作代表了一种安全，实用和可重复的方法，诱导持久的嵌合体和供体特异性耐受的实体器官移植受者。
The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSC) and tolerogenic CD8+/TCR− graft facilitating cells (FC) combined with nonmyeloablative conditioning that allows engraftment, durable chimerism, and tolerance induction in highly mismatched related and unrelated donor-recipient pairs. Eight recipients of HLA-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200 cGy total body irradiation, and cyclophosphamide followed by post-transplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from 5 of 6 related to 1 of 6 unrelated. The absolute neutrophil counts nadired approximately one week after transplant, with recovery by two weeks. Multilineage chimerism at one month was 6% to 100%. The conditioning was well tolerated with outpatient management after postoperative day two. Two subjects exhibited transient chimerism and have been reduced to low-dose tacrolimus monotherapy. One subject developed viral sepsis two months after transplant and experienced renal artery thrombosis. Five subjects have durable chimerism, with immunocompetence and donor-specific tolerance by in vitro proliferative assays and were successfully weaned off all immunosuppression one year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.
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影响因子：
20.3
作者：
Huang, Yiming;Bozulic, Larry D.;Ildstad, Suzanne T.
通讯作者：
Ildstad, Suzanne T.
影响因子：
3.8
作者：
ORLOFF, MS;DEMARA, EM;JORDAN, SC
通讯作者：
JORDAN, SC
影响因子：
2.6
作者：
Grimes, HL;Schanie, CL;Ildstad, ST
通讯作者：
Ildstad, ST
影响因子：
158.5
作者：
Ojo, AO;Held, PJ;Merion, RM
通讯作者：
Merion, RM
影响因子：
4.3
作者：
Gress, Ronald E.;Emerson, Stephen G.;Drobyski, William R.
通讯作者：
Drobyski, William R.