Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts.

Abstract

The role of the indirect allorecognition pathway in acute allograft rejection has been documented both in organ recipients and in experimental models. However, it is unknown whether self-restricted recognition of donor alloantigens also contributes to chronic allograft rejection. The aim of this study was to determine the relationship between allopeptide reactivity, epitope spreading, and chronic rejection. Using synthetic peptides corresponding to the hypervariable region of 32 HLA-DR alleles, we have followed the specificity of self-restricted T cell alloresponses to the donor in a population of 34 heart allograft recipients. T cells from sequential samples of blood collected from the patients up to 36 mo after transplantation were studied in limiting dilution analysis for allopeptide reactivity. The incidence of coronary artery vasculopathy (CAV) was significantly higher in patients who displayed persistent alloreactivity late after transplantation than in patients who showed no alloreactivity after the first 6 mo after transplantation. Both intra- and intermolecular spreading of epitopes was observed with an increased frequency in patients developing CAV in less than 2 yr, compared with patients without CAV; this suggests that diversification of the immune response against the graft contributes to chronic rejection. These data provide a strategy for identifying patients at risk of developing CAV and a rationale for therapeutic intervention aimed to prevent the progression of the rejection process.

Coronary Arteries from Human Cardiac Allografts with Chronic Rejection Contain Oligoclonal T Cells: Persistence of Identical Clonally Expanded TCR Transcripts from the Early Post-Transplantation Period (Endomyocardial Biopsies) to Chronic Rejection (Coronary Arteries)

“…A strong correlation has been reported (27,71) between donorspecific HLA-peptide alloreactivity of PBMC and the incidences of acute (27) and chronic rejection (71). The incidence of chronic a ␤-chain TCR transcripts were amplified by either NPA-PCR or V␤-specific PCR, and the amplified transcripts (see Table VIII) were cloned and sequenced.…”

“…rejection is much higher in patients with PBMC that continued to respond to donor HLA-DR peptides late after transplantation than in those without persistent PBMC alloreactivity (71). Intermolecular and intramolecular epitope spreading has been demonstrated in the proliferative responses of PBMC to synthetic peptides of the hypervariable region of 32 HLA-DR alleles (71,72).…”

“…Intermolecular and intramolecular epitope spreading has been demonstrated in the proliferative responses of PBMC to synthetic peptides of the hypervariable region of 32 HLA-DR alleles (71,72). Epitope spreading has been originally described in autoimmune demyelinating diseases of the CNS (73)(74)(75)(76)(77), and it is defined as the generation of de novo immune responses to epitopes different from and noncross-reacting to those that initially induced the immune response.…”

“…Epitope spreading has been originally described in autoimmune demyelinating diseases of the CNS (73)(74)(75)(76)(77), and it is defined as the generation of de novo immune responses to epitopes different from and noncross-reacting to those that initially induced the immune response. This definition (73)(74)(75)(76)(77) is extended now to the immunity against grafts (71,72) and to the immunity against tumors (78). Progression to chronicity in demyelinating autoimmune disorders and in graft rejection is associated with broadening the T cell repertoire with time (79).…”

Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

“…During the development of the alloimmune response, T cell specificity spreads to include new additional epitopes that were not targeted at the induction phase of the immune response [52]. B cells may play a pivotal role in such epitope spreading because of their potential in capturing and presenting additional donor or self epitopes required for T cell activation [53].…”