TY - JOUR
T1 - Corticosteroids and methotrexate as adjuvants to costimulation blockade in non-human primate renal transplantation
AU - Anderson, Douglas J.
AU - Lo, Denise J.
AU - Leopardi, Francis
AU - Song, Mingqing
AU - Strobert, Elizabeth A.
AU - Jenkins, Joe B.
AU - Larsen, Christian P.
AU - Kirk, Allan D.
N1 - Funding Information:
Funding for this research was provided by a grant from the NIH, 1U01AI079223, U01AI084150, and 2U19AI051731‐11. Further grant support of the Yerkes National Primate Research Center was provided by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132. Dr Anderson was partially supported by the ASTS‐Genentech Scientist Scholarship. The authors would like to thank the research support staff of the Emory Transplant Center and the veterinary staff at the Yerkes National Primate Research Center for their efforts on our behalf.
Funding Information:
Funding information Funding for this research was provided by a grant from the NIH, 1U01AI079223, U01AI084150, and 2U19AI051731-11. Further grant support of the Yerkes National Primate Research Center was provided by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132. Dr Anderson was partially supported by the ASTS-Genentech Scientist Scholarship. Funding for this research was provided by a grant from the NIH, 1U01AI079223, U01AI084150, and 2U19AI051731-11. Further grant support of the Yerkes National Primate Research Center was provided by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research Infrastructure Programs/OD P51OD11132. Dr Anderson was partially supported by the ASTS-Genentech Scientist Scholarship. The authors would like to thank the research support staff of the Emory Transplant Center and the veterinary staff at the Yerkes National Primate Research Center for their efforts on our behalf.
Funding Information:
Funding for this research was provided by a grant from the NIH, 1U01AI079223, U01AI084150, and 2U19AI051731‐11. Further grant support of the Yerkes National Primate Research Center was provided by the National Center for Research Resources P51RR165 and is currently supported by the Office of Research Infrastructure Programs/ OD P51OD11132. Dr Anderson was partially supported by the ASTS‐Genentech Scientist Scholarship.
Publisher Copyright:
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2019/6
Y1 - 2019/6
N2 - Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.
AB - Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.
KW - costimulation
KW - methotrexate
KW - non-human primate
UR - http://www.scopus.com/inward/record.url?scp=85065498449&partnerID=8YFLogxK
U2 - 10.1111/ctr.13568
DO - 10.1111/ctr.13568
M3 - Article
C2 - 31006146
AN - SCOPUS:85065498449
SN - 0902-0063
VL - 33
JO - Clinical Transplantation
JF - Clinical Transplantation
IS - 6
M1 - e13568
ER -