Oral feeding of an immunodominant MHC donor-derived synthetic class I peptide prolongs graft survival of heterotopic cardiac allografts in a high-responder rat strain combination.
The efficacy of two synthetic major histocompatibility complex (MHC)-derived DA (RT1.Aa) 25-mer peptides (residues 56-80 and 96-120) to modulate alloreactivity was tested in Lewis (RT1.A1) responder animals. The DA peptide 56-80, but not peptide 96-120, induced delayed-type hypersensitivity (DTH). DTH was significantly reduced by oral feeding of peptide 56-80, P = 0.004. In addition, oral feeding of this peptide in combination with a short course of cyclosporin A (CsA) prolonged graft survival of 60% of heterotope transplanted DA cardiac allografts in Lewis recipient rats. Long-term survivors developed low levels of allo-antibodies against donor tissue as compared to rejecting animals and increased levels of interleukin-4 (IL-4) within the allograft. Similarly, IL-4-secreting splenocytes were identified by flow cytometry in these animals, indicating a Th2-type cytokine pattern. However, graft survival was particularly limited to cardiac allografts because donor-type skin grafts were acutely rejected in tolerant animals. It is interesting that residue alignment of peptide 56-80 to the motif of the RT1.A1 molecule showed a preferred class I motif within this sequence, suggesting indirect presentation of this peptide to recipient T cells. Thus, peptide 56-80 appears to represent a dominant epitope that can be exploited for establishing tolerance in this transplantation strain combination.
Zavazava
N
N
Institute of Immunology and Department of General and Thoracic Surgery, University of Kiel, Germany. zavazava@immunologie.uni-kiel.de
Fändrich
F
F
Zhu
X
X
Freese
A
A
Behrens
D
D
Yoo-Ott
K A
KA
D000284:Administration, Oral; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D010455:Peptides; D015847:Interleukin-4