FK778 in experimental xenotransplantation: a detailed analysis of drug efficacy.
BACKGROUND
This study examines the efficacy of FK778 regimens for prevention of different phases of xenograft rejection.


METHODS
Antibody and complement tissue depositions were measured by immunofluorescence in a discordant ex vivo rat-to-human heart perfusion model of hyperacute rejection with immunosuppressant-enriched human blood. The concordant hamster-to-rat aortic xenotransplantation model was used to assess host cellular (lymphocyte activation, mixed lymphocyte reaction [MLR]) and humoral responsiveness (xenoantibody production) as well as histologic xenograft rejection. Recipients were treated for 14 days with FK778, tacrolimus, sirolimus or combination regimens at varying doses.


RESULTS
Antibody binding during hyperacute rejection was unaffected by the immunosuppressive treatment, but complement deposition was reduced in the following order: tacrolimus > FK778 approximately sirolimus. FK778 most effectively reduced complement factor 5 in vitro. In untreated rats with hamster aortic xenografts, a large infiltrative response was observed within the grafts with extensive myocyte necrosis. Tacrolimus > FK778 approximately sirolimus dose-dependently diminished xenograft infiltration and in the same order reduced vessel-wall myocyte necrosis. Tacrolimus approximately FK778 > sirolimus reduced in vivo lymphocyte CD25 expression and tacrolimus > FK778 approximately sirolimus diminished MLR. Xenoreactive IgM and IgG antibody production levels were vigorously upregulated a few days after transplantation, but were significantly reduced by tacrolimus > FK778 approximately sirolimus. Combination regimens revealed no significant benefit when compared with the corresponding monotherapy groups.


CONCLUSIONS
FK778 mildly interfered with hyperacute rejection and markedly suppressed acute humoral and cellular aortic xenograft rejection. However, T-cell-dependent host responses were most potently suppressed by tacrolimus, and the overall efficacy of FK778 was similar to that of sirolimus.
Schrepfer
Sonja
S
University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Deuse
Tobias
T
Koch-Nolte
Friedrich
F
Krieger
Thorsten
T
Haddad
Munif
M
Schäfer
Hansjörg
H
Pelletier
Marc P
MP
Robbins
Robert C
RC
Reichenspurner
Hermann
H
D000480:Alkynes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D001012:Aorta, Abdominal / Q000637:transplantation*; D006224:Cricetinae; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D009570:Nitriles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous / Q000379:methods*; D016896:Treatment Outcome
D000480:Alkynes; D000888:Antibodies, Anti-Idiotypic; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D053645:Interleukin-2 Receptor alpha Subunit; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide