FK778 in experimental xenotransplantation: a detailed analysis of drug efficacy.

Abstract

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.

• Authors: Sonja Schrepfer, Tobias Deuse, Friedrich Koch-Nolte, Thorsten Krieger, Munif Haddad, Hansjörg Schäfer, Marc P Pelletier, Robert C Robbins, Hermann Reichenspurner
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 26 Issue 1 Pg. 70-7 (Jan 2007) ISSN: 1557-3117 [Electronic] United States
• PMID: 17234520 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Antibodies, Anti-Idiotypic
• Immunoglobulin G
• Immunoglobulin M
• Interleukin-2 Receptor alpha Subunit
• Isoxazoles
• Nitriles
• 2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide

Topics

• Alkynes (pharmacokinetics, therapeutic use)
• Animals
• Antibodies, Anti-Idiotypic (immunology)
• Aorta, Abdominal (transplantation)
• Cricetinae
• Disease Models, Animal
• Endothelium, Vascular (pathology)
• Flow Cytometry
• Graft Rejection (immunology, pathology, prevention & control)
• Humans
• Immunoglobulin G (immunology)
• Immunoglobulin M (immunology)
• Interleukin-2 Receptor alpha Subunit (immunology)
• Isoxazoles (pharmacokinetics, therapeutic use)
• Male
• Nitriles (pharmacokinetics, therapeutic use)
• Rats
• Rats, Inbred BN
• Rats, Inbred Lew
• T-Lymphocytes (immunology)
• Transplantation, Heterologous (methods)
• Treatment Outcome