A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation

George E. Georges; Vladimir Lesnikov; Szczepan W. Baran; Anna Aragon; Marina Lesnikova; Robert Jordan; Ya Ju Laura Yang; Murad Y. Yunusov; Eustacia Zellmer; Shelly Heimfeld; Gopalakrishnan M. Venkataraman; Michael A. Harkey; Scott S. Graves; Rainer Storb; Barry E. Storer; Richard A. Nash

doi:10.1016/j.bbmt.2010.03.010

A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation

George E. Georges^*, Vladimir Lesnikov, Szczepan W. Baran, Anna Aragon, Marina Lesnikova, Robert Jordan, Ya Ju Laura Yang, Murad Y. Yunusov, Eustacia Zellmer, Shelly Heimfeld, Gopalakrishnan M. Venkataraman, Michael A. Harkey, Scott S. Graves, Rainer Storb, Barry E. Storer, Richard A. Nash

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

10 Scopus citations

Abstract

Cord blood transplantation (CBT) with units containing total nucleated cell (TNC) dose >2.5 × 10⁷/kg is associated with improved engraftment and decreased transplant-related mortality. For many adults no single cord blood units are available that meet the cell dose requirements. We developed a dog model of CBT to evaluate approaches to overcome the problem of low cell dose cord blood units. This study primarily compared double- versus single-unit CBT. Unrelated dogs were bred and cord blood units were harvested. We identified unrelated recipients that were dog leukocyte antigen (DLA)-88 (class I) and DLA-DRB1 (class II) allele-matched with cryopreserved units. Each unit contained ≤1.7 × 10⁷ TNC/kg. Recipients were given 9.2 Gy total-body irradiation (TBI) and DLA-matched unrelated cord blood with postgrafting cyclosporine and mycophenolate mofetil. After double-unit CBT, 5 dogs engrafted and 4 survived long term with 1 dominant engrafting unit and prompt immune reconstitution. In contrast, 0 of 5 dogs given single-unit CBT survived beyond 105 days (P = .03, log-rank test); neutrophil and platelet recovery was delayed (both P = .005) and recipients developed fatal infections. This new large animal model showed that outcomes were improved after double-unit compared to single-unit CBT. After double-unit CBT, the nonengrafted unit facilitates engraftment of the dominant unit.

Original language	English (US)
Pages (from-to)	1090-1098
Number of pages	9
Journal	Biology of Blood and Marrow Transplantation
Volume	16
Issue number	8
DOIs	https://doi.org/10.1016/j.bbmt.2010.03.010
State	Published - Aug 2010

Funding

Financial disclosure: The authors gratefully acknowledge the Veterinary supervision of Michele Spector, DVM, and all of the skilled animal technicians who provided surgical and medical care for the dogs, with special thanks to Marcia Hogan, Ausra Vastakas, Erin Hughes, Jennifer Gourley, and Jaime Newberry. We thank Chen-Han Lin, Patrice Stroup, David Yadock, Debe Higginbotham, Alla Nikitine, Billie Hwang, and Kraig Abrams for their technical assistance. We thank the physicians and postdoctoral investigators who volunteered and participated in weekend and after-hour care of the dogs including: Marco Mielcarek, David W. Mathes, Marcello Rotta, Maura Parker, Zejing Wang, Monica Thakar, Boglarka Gyurkocza, Mohammed Sorror, Yasuhiro Suzuki, Zhen Yan, Xiaobing Zhang, Hirohisa Nakamae, Won Sik Lee, Hans-Peter Kiem, Joerg Enssle, Jaakko V. Parkkinen, and Brian Beard. We also thank Bonnie Larson, Helen Crawford, and Sue Carbonneau for help with manuscript preparation. We thank Dr. Beverly Torok-Storb for her review of the manuscript. Amgen kindly provided recombinant canine G-CSF. Funding was provided from the National Institutes of Health, National Institute for Allergy and Infectious Disease , Grant U19 AI 067770 , Centers for Medical Countermeasures against Radiation. Additional support was provided by NIH Grants CA15704, CA78902 , and DK42716 .

Keywords

Cord blood transplantation
Dog model
Graft failure
Immune reconstitution
Unrelated donor

ASJC Scopus subject areas

Transplantation
Hematology

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10.1016/j.bbmt.2010.03.010

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Georges, G. E., Lesnikov, V., Baran, S. W., Aragon, A., Lesnikova, M., Jordan, R., Laura Yang, Y. J., Yunusov, M. Y., Zellmer, E., Heimfeld, S., Venkataraman, G. M., Harkey, M. A., Graves, S. S., Storb, R., Storer, B. E., & Nash, R. A. (2010). A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation. Biology of Blood and Marrow Transplantation, 16(8), 1090-1098. https://doi.org/10.1016/j.bbmt.2010.03.010

@article{a0cb40cba31648a187761172e96b462e,

title = "A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation",

abstract = "Cord blood transplantation (CBT) with units containing total nucleated cell (TNC) dose >2.5 × 107/kg is associated with improved engraftment and decreased transplant-related mortality. For many adults no single cord blood units are available that meet the cell dose requirements. We developed a dog model of CBT to evaluate approaches to overcome the problem of low cell dose cord blood units. This study primarily compared double- versus single-unit CBT. Unrelated dogs were bred and cord blood units were harvested. We identified unrelated recipients that were dog leukocyte antigen (DLA)-88 (class I) and DLA-DRB1 (class II) allele-matched with cryopreserved units. Each unit contained ≤1.7 × 107 TNC/kg. Recipients were given 9.2 Gy total-body irradiation (TBI) and DLA-matched unrelated cord blood with postgrafting cyclosporine and mycophenolate mofetil. After double-unit CBT, 5 dogs engrafted and 4 survived long term with 1 dominant engrafting unit and prompt immune reconstitution. In contrast, 0 of 5 dogs given single-unit CBT survived beyond 105 days (P = .03, log-rank test); neutrophil and platelet recovery was delayed (both P = .005) and recipients developed fatal infections. This new large animal model showed that outcomes were improved after double-unit compared to single-unit CBT. After double-unit CBT, the nonengrafted unit facilitates engraftment of the dominant unit.",

keywords = "Cord blood transplantation, Dog model, Graft failure, Immune reconstitution, Unrelated donor",

author = "Georges, {George E.} and Vladimir Lesnikov and Baran, {Szczepan W.} and Anna Aragon and Marina Lesnikova and Robert Jordan and {Laura Yang}, {Ya Ju} and Yunusov, {Murad Y.} and Eustacia Zellmer and Shelly Heimfeld and Venkataraman, {Gopalakrishnan M.} and Harkey, {Michael A.} and Graves, {Scott S.} and Rainer Storb and Storer, {Barry E.} and Nash, {Richard A.}",

note = "Funding Information: Financial disclosure: The authors gratefully acknowledge the Veterinary supervision of Michele Spector, DVM, and all of the skilled animal technicians who provided surgical and medical care for the dogs, with special thanks to Marcia Hogan, Ausra Vastakas, Erin Hughes, Jennifer Gourley, and Jaime Newberry. We thank Chen-Han Lin, Patrice Stroup, David Yadock, Debe Higginbotham, Alla Nikitine, Billie Hwang, and Kraig Abrams for their technical assistance. We thank the physicians and postdoctoral investigators who volunteered and participated in weekend and after-hour care of the dogs including: Marco Mielcarek, David W. Mathes, Marcello Rotta, Maura Parker, Zejing Wang, Monica Thakar, Boglarka Gyurkocza, Mohammed Sorror, Yasuhiro Suzuki, Zhen Yan, Xiaobing Zhang, Hirohisa Nakamae, Won Sik Lee, Hans-Peter Kiem, Joerg Enssle, Jaakko V. Parkkinen, and Brian Beard. We also thank Bonnie Larson, Helen Crawford, and Sue Carbonneau for help with manuscript preparation. We thank Dr. Beverly Torok-Storb for her review of the manuscript. Amgen kindly provided recombinant canine G-CSF. Funding was provided from the National Institutes of Health, National Institute for Allergy and Infectious Disease , Grant U19 AI 067770 , Centers for Medical Countermeasures against Radiation. Additional support was provided by NIH Grants CA15704, CA78902 , and DK42716 . ",

year = "2010",

month = aug,

doi = "10.1016/j.bbmt.2010.03.010",

language = "English (US)",

volume = "16",

pages = "1090--1098",

journal = "Biology of Blood and Marrow Transplantation",

issn = "1083-8791",

publisher = "Elsevier Inc.",

number = "8",

}

Georges, GE, Lesnikov, V, Baran, SW, Aragon, A, Lesnikova, M, Jordan, R, Laura Yang, YJ, Yunusov, MY, Zellmer, E, Heimfeld, S, Venkataraman, GM, Harkey, MA, Graves, SS, Storb, R, Storer, BE & Nash, RA 2010, 'A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation', Biology of Blood and Marrow Transplantation, vol. 16, no. 8, pp. 1090-1098. https://doi.org/10.1016/j.bbmt.2010.03.010

TY - JOUR

T1 - A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation

AU - Georges, George E.

AU - Lesnikov, Vladimir

AU - Baran, Szczepan W.

AU - Aragon, Anna

AU - Lesnikova, Marina

AU - Jordan, Robert

AU - Laura Yang, Ya Ju

AU - Yunusov, Murad Y.

AU - Zellmer, Eustacia

AU - Heimfeld, Shelly

AU - Venkataraman, Gopalakrishnan M.

AU - Harkey, Michael A.

AU - Graves, Scott S.

AU - Storb, Rainer

AU - Storer, Barry E.

AU - Nash, Richard A.

N1 - Funding Information: Financial disclosure: The authors gratefully acknowledge the Veterinary supervision of Michele Spector, DVM, and all of the skilled animal technicians who provided surgical and medical care for the dogs, with special thanks to Marcia Hogan, Ausra Vastakas, Erin Hughes, Jennifer Gourley, and Jaime Newberry. We thank Chen-Han Lin, Patrice Stroup, David Yadock, Debe Higginbotham, Alla Nikitine, Billie Hwang, and Kraig Abrams for their technical assistance. We thank the physicians and postdoctoral investigators who volunteered and participated in weekend and after-hour care of the dogs including: Marco Mielcarek, David W. Mathes, Marcello Rotta, Maura Parker, Zejing Wang, Monica Thakar, Boglarka Gyurkocza, Mohammed Sorror, Yasuhiro Suzuki, Zhen Yan, Xiaobing Zhang, Hirohisa Nakamae, Won Sik Lee, Hans-Peter Kiem, Joerg Enssle, Jaakko V. Parkkinen, and Brian Beard. We also thank Bonnie Larson, Helen Crawford, and Sue Carbonneau for help with manuscript preparation. We thank Dr. Beverly Torok-Storb for her review of the manuscript. Amgen kindly provided recombinant canine G-CSF. Funding was provided from the National Institutes of Health, National Institute for Allergy and Infectious Disease , Grant U19 AI 067770 , Centers for Medical Countermeasures against Radiation. Additional support was provided by NIH Grants CA15704, CA78902 , and DK42716 .

PY - 2010/8

Y1 - 2010/8

N2 - Cord blood transplantation (CBT) with units containing total nucleated cell (TNC) dose >2.5 × 107/kg is associated with improved engraftment and decreased transplant-related mortality. For many adults no single cord blood units are available that meet the cell dose requirements. We developed a dog model of CBT to evaluate approaches to overcome the problem of low cell dose cord blood units. This study primarily compared double- versus single-unit CBT. Unrelated dogs were bred and cord blood units were harvested. We identified unrelated recipients that were dog leukocyte antigen (DLA)-88 (class I) and DLA-DRB1 (class II) allele-matched with cryopreserved units. Each unit contained ≤1.7 × 107 TNC/kg. Recipients were given 9.2 Gy total-body irradiation (TBI) and DLA-matched unrelated cord blood with postgrafting cyclosporine and mycophenolate mofetil. After double-unit CBT, 5 dogs engrafted and 4 survived long term with 1 dominant engrafting unit and prompt immune reconstitution. In contrast, 0 of 5 dogs given single-unit CBT survived beyond 105 days (P = .03, log-rank test); neutrophil and platelet recovery was delayed (both P = .005) and recipients developed fatal infections. This new large animal model showed that outcomes were improved after double-unit compared to single-unit CBT. After double-unit CBT, the nonengrafted unit facilitates engraftment of the dominant unit.

AB - Cord blood transplantation (CBT) with units containing total nucleated cell (TNC) dose >2.5 × 107/kg is associated with improved engraftment and decreased transplant-related mortality. For many adults no single cord blood units are available that meet the cell dose requirements. We developed a dog model of CBT to evaluate approaches to overcome the problem of low cell dose cord blood units. This study primarily compared double- versus single-unit CBT. Unrelated dogs were bred and cord blood units were harvested. We identified unrelated recipients that were dog leukocyte antigen (DLA)-88 (class I) and DLA-DRB1 (class II) allele-matched with cryopreserved units. Each unit contained ≤1.7 × 107 TNC/kg. Recipients were given 9.2 Gy total-body irradiation (TBI) and DLA-matched unrelated cord blood with postgrafting cyclosporine and mycophenolate mofetil. After double-unit CBT, 5 dogs engrafted and 4 survived long term with 1 dominant engrafting unit and prompt immune reconstitution. In contrast, 0 of 5 dogs given single-unit CBT survived beyond 105 days (P = .03, log-rank test); neutrophil and platelet recovery was delayed (both P = .005) and recipients developed fatal infections. This new large animal model showed that outcomes were improved after double-unit compared to single-unit CBT. After double-unit CBT, the nonengrafted unit facilitates engraftment of the dominant unit.

KW - Cord blood transplantation

KW - Dog model

KW - Graft failure

KW - Immune reconstitution

KW - Unrelated donor

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A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation

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