Acellular Normothermic Machine Perfusion Does not Exacerbate Acute Rejection in Rodent Vascularized Composite Allografts

Irina Filz von Reiterdank; Raphaela Bento; Eloi de Clermont-Tonnerre; Antonia T Dinicu; Hyshem H Lancia; Michelle E McCarthy; Alexandre G Lellouch; Basak E Uygun; Curtis L Cetrulo; J Henk Coert; Aebele B Mink van der Molen; Biju Parekkadan; Korkut Uygun

doi:10.1097/TXD.0000000000001950

Acellular Normothermic Machine Perfusion Does not Exacerbate Acute Rejection in Rodent Vascularized Composite Allografts

Irina Filz von Reiterdank
, Raphaela Bento
, Eloi de Clermont-Tonnerre
, Antonia T Dinicu
, Hyshem H Lancia
, Michelle E McCarthy
, Alexandre G Lellouch
, Basak E Uygun
, Curtis L Cetrulo
, J Henk Coert
, Aebele B Mink van der Molen
, Biju Parekkadan^*
, Korkut Uygun^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Vascularized composite allotransplantation faces significant challenges, including limited preservation time and high rates of acute rejection because of the ischemia susceptibility of muscle and immunogenicity of skin. However, no studies have investigated whether normothermic machine perfusion (NMP) has an effect on acute rejection compared with static cold storage (SCS).

METHODS: Heterotopic hindlimb transplants were performed in a full-mismatch model after 6 h of SCS or NMP. Postoperative assessments included clinical scoring, histological examination, cytokine profiling, and flow cytometry of splenocytes and lymphocytes at the end of the study.

RESULTS: Clinical assessment revealed significantly lower rejection scores in the NMP group on postoperative day (POD) 2 (P = 0.03). Notably, histology indicated delayed rejection, with Banff scores showing severe rejection from POD2 in the SCS group and from POD6 in the NMP group. Cytokine profiling demonstrated early upregulation of anti-inflammatory interleukin-10 in the NMP group at POD1, and flow cytometry showed a reduction in B cell populations.

CONCLUSIONS: While NMP is not a cure-all, it is associated with a delayed onset of acute rejection compared with SCS in a full-mismatch rodent vascularized composite allotransplantation model. Future studies should focus on analysis earlier in the rejection process and on long-term graft survival to further elucidate the mechanism of the effect of NMP on the immune response.

Original language	English
Article number	e1950
Journal	Transplantation direct
Volume	12
Issue number	6
DOIs	https://doi.org/10.1097/TXD.0000000000001950
Publication status	Published - Jun 2026

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Filz von Reiterdank, I., Bento, R., de Clermont-Tonnerre, E., Dinicu, A. T., Lancia, H. H., McCarthy, M. E., Lellouch, A. G., Uygun, B. E., Cetrulo, C. L., Coert, J. H., Mink van der Molen, A. B., Parekkadan, B., & Uygun, K. (2026). Acellular Normothermic Machine Perfusion Does not Exacerbate Acute Rejection in Rodent Vascularized Composite Allografts. Transplantation direct, 12(6), Article e1950. https://doi.org/10.1097/TXD.0000000000001950

@article{4061f3508e234bad89294223548a143d,

title = "Acellular Normothermic Machine Perfusion Does not Exacerbate Acute Rejection in Rodent Vascularized Composite Allografts",

abstract = "BACKGROUND: Vascularized composite allotransplantation faces significant challenges, including limited preservation time and high rates of acute rejection because of the ischemia susceptibility of muscle and immunogenicity of skin. However, no studies have investigated whether normothermic machine perfusion (NMP) has an effect on acute rejection compared with static cold storage (SCS).METHODS: Heterotopic hindlimb transplants were performed in a full-mismatch model after 6 h of SCS or NMP. Postoperative assessments included clinical scoring, histological examination, cytokine profiling, and flow cytometry of splenocytes and lymphocytes at the end of the study.RESULTS: Clinical assessment revealed significantly lower rejection scores in the NMP group on postoperative day (POD) 2 (P = 0.03). Notably, histology indicated delayed rejection, with Banff scores showing severe rejection from POD2 in the SCS group and from POD6 in the NMP group. Cytokine profiling demonstrated early upregulation of anti-inflammatory interleukin-10 in the NMP group at POD1, and flow cytometry showed a reduction in B cell populations.CONCLUSIONS: While NMP is not a cure-all, it is associated with a delayed onset of acute rejection compared with SCS in a full-mismatch rodent vascularized composite allotransplantation model. Future studies should focus on analysis earlier in the rejection process and on long-term graft survival to further elucidate the mechanism of the effect of NMP on the immune response.",

author = "\{Filz von Reiterdank\}, Irina and Raphaela Bento and \{de Clermont-Tonnerre\}, Eloi and Dinicu, \{Antonia T\} and Lancia, \{Hyshem H\} and McCarthy, \{Michelle E\} and Lellouch, \{Alexandre G\} and Uygun, \{Basak E\} and Cetrulo, \{Curtis L\} and Coert, \{J Henk\} and \{Mink van der Molen\}, \{Aebele B\} and Biju Parekkadan and Korkut Uygun",

note = "Copyright {\textcopyright} 2026 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.",

year = "2026",

month = jun,

doi = "10.1097/TXD.0000000000001950",

language = "English",

volume = "12",

journal = "Transplantation direct",

issn = "2373-8731",

publisher = "Wolters Kluwer Health",

number = "6",

}

Filz von Reiterdank, I, Bento, R, de Clermont-Tonnerre, E, Dinicu, AT, Lancia, HH, McCarthy, ME, Lellouch, AG, Uygun, BE, Cetrulo, CL, Coert, JH, Mink van der Molen, AB, Parekkadan, B & Uygun, K 2026, 'Acellular Normothermic Machine Perfusion Does not Exacerbate Acute Rejection in Rodent Vascularized Composite Allografts', Transplantation direct, vol. 12, no. 6, e1950. https://doi.org/10.1097/TXD.0000000000001950

TY - JOUR

T1 - Acellular Normothermic Machine Perfusion Does not Exacerbate Acute Rejection in Rodent Vascularized Composite Allografts

AU - Filz von Reiterdank, Irina

AU - Bento, Raphaela

AU - de Clermont-Tonnerre, Eloi

AU - Dinicu, Antonia T

AU - Lancia, Hyshem H

AU - McCarthy, Michelle E

AU - Lellouch, Alexandre G

AU - Uygun, Basak E

AU - Cetrulo, Curtis L

AU - Coert, J Henk

AU - Mink van der Molen, Aebele B

AU - Parekkadan, Biju

AU - Uygun, Korkut

PY - 2026/6

Y1 - 2026/6

N2 - BACKGROUND: Vascularized composite allotransplantation faces significant challenges, including limited preservation time and high rates of acute rejection because of the ischemia susceptibility of muscle and immunogenicity of skin. However, no studies have investigated whether normothermic machine perfusion (NMP) has an effect on acute rejection compared with static cold storage (SCS).METHODS: Heterotopic hindlimb transplants were performed in a full-mismatch model after 6 h of SCS or NMP. Postoperative assessments included clinical scoring, histological examination, cytokine profiling, and flow cytometry of splenocytes and lymphocytes at the end of the study.RESULTS: Clinical assessment revealed significantly lower rejection scores in the NMP group on postoperative day (POD) 2 (P = 0.03). Notably, histology indicated delayed rejection, with Banff scores showing severe rejection from POD2 in the SCS group and from POD6 in the NMP group. Cytokine profiling demonstrated early upregulation of anti-inflammatory interleukin-10 in the NMP group at POD1, and flow cytometry showed a reduction in B cell populations.CONCLUSIONS: While NMP is not a cure-all, it is associated with a delayed onset of acute rejection compared with SCS in a full-mismatch rodent vascularized composite allotransplantation model. Future studies should focus on analysis earlier in the rejection process and on long-term graft survival to further elucidate the mechanism of the effect of NMP on the immune response.

AB - BACKGROUND: Vascularized composite allotransplantation faces significant challenges, including limited preservation time and high rates of acute rejection because of the ischemia susceptibility of muscle and immunogenicity of skin. However, no studies have investigated whether normothermic machine perfusion (NMP) has an effect on acute rejection compared with static cold storage (SCS).METHODS: Heterotopic hindlimb transplants were performed in a full-mismatch model after 6 h of SCS or NMP. Postoperative assessments included clinical scoring, histological examination, cytokine profiling, and flow cytometry of splenocytes and lymphocytes at the end of the study.RESULTS: Clinical assessment revealed significantly lower rejection scores in the NMP group on postoperative day (POD) 2 (P = 0.03). Notably, histology indicated delayed rejection, with Banff scores showing severe rejection from POD2 in the SCS group and from POD6 in the NMP group. Cytokine profiling demonstrated early upregulation of anti-inflammatory interleukin-10 in the NMP group at POD1, and flow cytometry showed a reduction in B cell populations.CONCLUSIONS: While NMP is not a cure-all, it is associated with a delayed onset of acute rejection compared with SCS in a full-mismatch rodent vascularized composite allotransplantation model. Future studies should focus on analysis earlier in the rejection process and on long-term graft survival to further elucidate the mechanism of the effect of NMP on the immune response.

U2 - 10.1097/TXD.0000000000001950

DO - 10.1097/TXD.0000000000001950

M3 - Article

C2 - 42110836

SN - 2373-8731

VL - 12

JO - Transplantation direct

JF - Transplantation direct

IS - 6

M1 - e1950

ER -

Acellular Normothermic Machine Perfusion Does not Exacerbate Acute Rejection in Rodent Vascularized Composite Allografts

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