Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies.
Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies.
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DOI：
10.1016/j.xcrm.2023.101336
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发表时间：
2023-12-19
影响因子：
14.3
通讯作者：
Bhoj, Vijay G.
中科院分区：
文献类型：
--
作者：
Zhang, Zheng;Markmann, Caroline;Yu, Ming;Agarwal, Divyansh;Rostami, Susan;Wang, Wei;Liu, Chengyang;Zhao, Huiwu;Ochoa, Trini;Parvathaneni, Kalpana;Xu, Xiaoming;Li, Eric;Gonzalez, Vanessa;Khadka, Roman;Hoffmann, Jennifer;Knox, James J.;Scholler, John;Marcellus, Brooke;Allman, David;Fraietta, Joseph A.;Samelson-Jones, Benjamin;Milone, Michael C.;Monos, Dimitri;Garfall, Alfred L.;Naji, Ali;Bhoj, Vijay G.
预先存在的抗人白细胞抗原(HLA)同种抗体构成了移植的主要障碍。目前的脱敏方法由于同种异体特异性记忆B细胞(BMems)和长寿浆细胞(LLPC)的无效耗尽而失败。我们评价了针对CD19和B细胞成熟抗原(BCMA)的嵌合抗原受体(CAR)T细胞在同种异体胰岛移植皮肤预致敏小鼠模型中消除同种抗体的效果。我们发现，用针对Bems和LLPC的CAR T细胞治疗同种异体致敏宿主可以消除供者特异性同种异体抗体(DSA)，并减轻随后同种异体胰岛移植的超急性排斥反应。然后，我们评估了CART-BCMA和CART-19联合治疗的多发性骨髓瘤(MM)患者使用CART-BCMA和CART-19(ClinicalTrials.gov：NCT03549442)进行脱敏治疗的临床疗效，并观察了有临床意义的同种抗体减少。这些发现为临床评估基于CAR T的免疫疗法在高度致敏的候选人中促进移植成功提供了合理的理论基础。CD19+BMems和CD19−LLPC是先前存在的同种抗体的细胞来源，Cart-19+Cart-BCMA消除Bems、LLPC和同种抗体并防止AMR Cart-19+Cart-BCMA消除人类中的同种抗体针对CD19+BCMA的免疫疗法代表着很有前途的脱敏策略。郑等人。证明CART-19和CART-BCMA/TACI消除了这些细胞并使小鼠脱敏，从而减轻了移植排斥反应。初步结果也表明，该药对人体有效。他们的研究支持针对BCMA和CD19的免疫疗法的临床评估，以使高度致敏的移植候选人脱敏。
Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation. CD19+ Bmems and CD19− LLPCs are cellular sources of pre-existing allo-antibodies CART-19 + CART-BCMA eliminate Bmems, LLPCs, and allo-antibodies and prevent AMR CART-19 + CART-BCMA eliminate allo-antibodies in humans Immunotherapies targeting CD19 + BCMA represent promising desensitization strategies Bmems and LLPCs maintain allo-antibodies that present barriers to transplantation. Zheng et al. demonstrate that CART-19 and CART-BCMA/TACI eliminate these cells and desensitize mice, mitigating transplant rejection. Preliminary results also suggest efficacy in humans. Their study supports clinical evaluation of immunotherapies targeting BCMA and CD19 to desensitize highly sensitized transplant candidates.
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影响因子：
3.7
作者：
Yusuf I;Stern J;McCaughtry TM;Gallagher S;Sun H;Gao C;Tedder T;Carlesso G;Carter L;Herbst R;Wang Y
通讯作者：
Wang Y
影响因子：
11.2
作者：
通讯作者：
--
影响因子：
17.1
作者：
Crickx E;Chappert P;Sokal A;Weller S;Azzaoui I;Vandenberghe A;Bonnard G;Rossi G;Fadeev T;Storck S;Fadlallah J;Meignin V;Rivière E;Audia S;Godeau B;Michel M;Weill JC;Reynaud CA;Mahévas M
通讯作者：
Mahévas M
DOI：
10.4049/jimmunol.2200542
发表时间：
2022-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Muralidharan K;Agarwal D;Naji A;Bhoj VG
通讯作者：
Bhoj VG
影响因子：
8
作者：
Dawson, Nicholas A. J.;Lamarche, Caroline;Levings, Megan K.
通讯作者：
Levings, Megan K.