Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts

TY - JOUR

T1 - Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts

AU - Brown, K

AU - Nowocin, A K

AU - Meader, L

AU - Edwards, L A

AU - Smith, R A

AU - Wong, W

N1 - © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

PY - 2016/4

Y1 - 2016/4

N2 - Rejection of donor organs depends on the trafficking of donor passenger leukocytes to the secondary lymphoid organs of the recipient to elicit an immune response via the direct antigen presentation pathway. Therefore, the depletion of passenger leukocytes may be clinically applicable as a strategy to improve graft survival. Because major histocompatibility complex (MHC) class II(+) cells are most efficient at inducing immune responses, selective depletion of this population from donor grafts may dampen the alloimmune response and prolong graft survival. In a fully MHC mismatched mouse kidney allograft model, we describe the synthesis of an immunotoxin, consisting of the F(ab')2 fragment of a monoclonal antibody against the donor MHC class II molecule I-A(k) conjugated with the plant-derived ribosomal inactivating protein gelonin. This anti-I-A(k) gelonin immunotoxin depletes I-A(k) expressing cells specifically in vitro and in vivo. When given to recipients of kidney allografts, it resulted in indefinite graft survival with normal graft function, presence of Foxp3(+) cells within donor grafts, diminished donor-specific antibody formation, and delayed rejection of subsequent donor-type skin grafts. Strategies aimed at the donor arm of the immune system using agents such as immunotoxins may be a useful adjuvant to existing recipient-orientated immunosuppression.

AB - Rejection of donor organs depends on the trafficking of donor passenger leukocytes to the secondary lymphoid organs of the recipient to elicit an immune response via the direct antigen presentation pathway. Therefore, the depletion of passenger leukocytes may be clinically applicable as a strategy to improve graft survival. Because major histocompatibility complex (MHC) class II(+) cells are most efficient at inducing immune responses, selective depletion of this population from donor grafts may dampen the alloimmune response and prolong graft survival. In a fully MHC mismatched mouse kidney allograft model, we describe the synthesis of an immunotoxin, consisting of the F(ab')2 fragment of a monoclonal antibody against the donor MHC class II molecule I-A(k) conjugated with the plant-derived ribosomal inactivating protein gelonin. This anti-I-A(k) gelonin immunotoxin depletes I-A(k) expressing cells specifically in vitro and in vivo. When given to recipients of kidney allografts, it resulted in indefinite graft survival with normal graft function, presence of Foxp3(+) cells within donor grafts, diminished donor-specific antibody formation, and delayed rejection of subsequent donor-type skin grafts. Strategies aimed at the donor arm of the immune system using agents such as immunotoxins may be a useful adjuvant to existing recipient-orientated immunosuppression.

KW - Allografts

KW - Animals

KW - Antibodies, Monoclonal/pharmacology

KW - Cytotoxicity, Immunologic/drug effects

KW - Female

KW - Flow Cytometry

KW - Graft Rejection/etiology

KW - Graft Survival/immunology

KW - Histocompatibility Antigens Class II/immunology

KW - Immune Tolerance/immunology

KW - Immunotoxins/pharmacology

KW - Kidney Transplantation

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C3H

KW - Mice, Inbred C57BL

KW - Ribosome Inactivating Proteins, Type 1/chemistry

KW - Tissue Donors

U2 - 10.1111/ajt.13584

DO - 10.1111/ajt.13584

M3 - Article

C2 - 26799449

SN - 1600-6135

VL - 16

SP - 1129

EP - 1138

JO - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

JF - American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

IS - 4

ER -