Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.
Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.
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DOI：
10.1016/j.kint.2020.08.020
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发表时间：
2021-01
影响因子：
19.6
通讯作者：
Knechtle SJ
中科院分区：
文献类型：
--
作者：
Schroder PM;Schmitz R;Fitch ZW;Ezekian B;Yoon J;Choi AY;Manook M;Barbas A;Leopardi F;Song M;Farris AB;Collins B;Kwun J;Knechtle SJ
Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4+PD-1+ICOS+), and proliferating B cells (CD20+Ki67+) in the lymph nodes. Interestingly, regulatory T cell (CD4+CD25+CD127lo) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7+CD45RA+) and naïve B cells (IgD+CD27−CD20+) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system to a more naive phenotype. This regimen may translate into clinical practice to improve outcomes of highly sensitized transplant patients.
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DOI：
10.1111/ajt.13688
发表时间：
2016-06
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Burghuber CK;Kwun J;Page EJ;Manook M;Gibby AC;Leopardi FV;Song M;Farris AB 3rd;Hong JJ;Villinger F;Adams AB;Iwakoshi NN;Knechtle SJ
通讯作者：
Knechtle SJ
DOI：
10.1111/ajt.14400
发表时间：
2018-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Badell IR;La Muraglia GM 2nd;Liu D;Wagener ME;Ding G;Ford ML
通讯作者：
Ford ML
影响因子：
13.6
作者：
Kwun, Jean;Burghuber, Christopher;Knechtle, Stuart
通讯作者：
Knechtle, Stuart
影响因子：
8.8
作者：
Poirier, N.;Dilek, N.;Blancho, G.
通讯作者：
Blancho, G.
影响因子：
17.1
作者：
Poirier, Nicolas;Azimzadeh, Agnes M.;Vanhove, Bernard
通讯作者：
Vanhove, Bernard