Intermittent antibody-based combination therapy removes alloantibodies and achieves indefinite heart transplant survival in presensitized recipients.
BACKGROUND
It is well established that primed/memory T cells play a critical role in heart transplant rejection. This contributes to the challenges faced in the transplant clinic because current treatments that are efficient in controlling naïve T cell alloresponses have limited efficacy on primed T cell responders.


METHODS
Fully MHC-mismatched heart transplantation was performed from BALB/c to C57BL/6 mice presensitized with BALB/c splenocytes 14 days pretransplantation. A combination therapy comprising CD70-, CD154-, and CD8-specific antibodies (Abs) was administered at day 0 and 4 posttransplantation with rapamycin on days 0 to 4.


RESULTS
The Ab combination therapy extended heart transplant survival in presensitized recipients from median survival time 8 days (MST) to MST 78 days. A decrease in the number of splenic interferon-gamma-secreting cells measured by ELISpot assay was seen in the treated group compared with the untreated controls. However, graft-infiltrating CD8+ and CD4+ T cells persisted despite treatment and the number of intragraft CD4+ T cells increased at day 30 posttransplantation. When an additional "rescue therapy" comprising the same Abs was readministered at days 30, 60, and 90 posttransplantation, T cell infiltration was reduced and indefinite graft survival was observed. Furthermore, rescue therapy resulted in gradual decrease in titer and, by day 90 posttransplantation, the complete loss of the preexisting, donor-specific Abs.


CONCLUSIONS
We conclude that our Ab combination therapy extends allograft survival in presensitized recipients. When combined with intermittent Ab-mediated rescue therapy, this results in indefinite allograft survival and a loss of the preexisting, donor-specific Abs from the circulation.
Shariff
Hina
H
Department of Nephrology and Transplantation, King's College London, Guy's Hospital, London, United Kingdom.
Tanriver
Yakup
Y
Brown
Kathryn L
KL
Meader
Lucy
L
Greenlaw
Roseanna
R
Mamode
Nizam
N
Jurcevic
Stipo
S
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D053282:CD27 Ligand / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D004359:Drug Therapy, Combination; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D006648:Histocompatibility; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D020123:Sirolimus / Q000627:therapeutic use; D013154:Spleen / Q000276:immunology / Q000637:transplantation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects*; D016896:Treatment Outcome
D000906:Antibodies; D053282:CD27 Ligand; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D007518:Isoantibodies; D023201:CD40 Ligand; D007371:Interferon-gamma; D020123:Sirolimus