Pathways of allorecognition: implications for transplantation tolerance

The immune system has the daunting task of distinguishing between self and non-self. The mucosal immune system, present along the respiratory, gastrointestinal and genitourinary tracts, has the additional burden of coexisting with an abundance of dietary antigens and lumenal bacterial flora. A key feature of the mucosal immune system is its ability to remain tolerant to these antigens while retaining the capacity to repel pathogens effectively. Furthermore, tolerance generated at mucosal surfaces can translate to a more generalized systemic tolerance — a characteristic of great therapeutic potential, but with many unforeseen complexities that are explored in this review.

Therapeutic potential of oral tolerance

We have previously reported that oral administration of allogeneic rat spleen cells before kidney allotransplantation significantly prolongs graft survival. This prolongation was alloantigen specific and was associated with a decrease in graft-infiltrating cells (GIC) and an increase in transcription of IL-4 mRNA in the GIC. In this study increased splenic mixed lymphocyte responses from animals orally exposed to alloantigen before kidney transplantation suggested that the kidney allograft prolongation was not due to a masking of allorecognition, but to an immunomodulation of the immune response. We have assessed GIC T cell subsets on day 5 post-transplant and found decreased numbers of CD4(+) T cells in fed animals compared with controls, but there was no change in CD8(+) T cell numbers. The CD8(+) GIC from fed animals transcribed substantial levels of perforin, granzyme, and Fas ligand mRNA, indicating the presence of active CTL. Direct CTL assays showed that the GIC from fed recipients exhibited higher allo-CTL activity than GIC from control unfed recipients. In addition, the CD8(+) GIC exhibited high levels of IL-4 mRNA, suggesting Tc2-type regulatory cells. Prolonged graft survival in the face of active CTL and Tc2 cells suggests the presence of a CD8(+) regulatory cell population in the allograft. To confirm this, cell transfer experiments were performed. Prolongation of graft survival was transferred from rats orally exposed to alloantigen to naive animals by transfer of CD8(+) GIC. This is the first report that oral exposure to alloantigen prolongs kidney allograft survival by the generation of intragraft CD8(+) regulatory cells.

Oral Exposure to Alloantigen Generates Intragraft CD8+ Regulatory Cells

Immune regulation by regulatory T cells: implications for transplantation.

Purpose of review Oral tolerance refers to the ability of the mucosal immune system to actively inhibit systemic immune responses to fed antigens. Recently, clinical trials have used oral tolerance as a therapy for certain chronic inflammatory and autoimmune diseases such as multiple sclerosis and type I diabetes. Inflammatory bowel disease is now widely thought to be caused by the breakdown of oral tolerance through a combination of genetic and environmental factors. Therefore, it seems incongruous that clinicians would try to use oral tolerance therapy to alleviate the symptoms of inflammatory bowel disease. Yet, armed with the results of select animal models, trials have begun for oral tolerance therapy for Crohn's disease. This review will outline the recent advances in understanding oral tolerance, explore the relation between oral tolerance and inflammatory bowel disease, and comment on the likelihood of successful oral tolerance therapy for inflammatory bowel disease. Recent findings The results of an oral tolerance trial in Crohn's disease patients in Israel have shown some promising results, whereas the results of studies of experimentally induced oral tolerance in patients with inflammatory bowel disease from the authors' laboratory have shown that feeding a neoantigen in an attempt to induce oral tolerance is not successful in patients with inflammatory bowel disease. Summary The fundamental difference in the mechanisms of oral tolerance in mice and humans requires a more focused effort to understand the human mucosal immune system before oral tolerance therapy for autoimmune and chronic inflammatory disorders reaches its full potential.

Oral tolerance and inflammatory bowel disease.

The efficacy of two synthetic major histocompatibility complex (MHC)-derived DA (RT1.A a ) 25-mer peptides (residues 56-80 and 96-120) to modulate alloreactivity was tested in Lewis (RT1.A 1 ) 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 5 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 het- erotope 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. Simi- larly, 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 align- ment of peptide 56-80 to the motif of the RT1.A 1 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. J. Leukoc. Biol. 67: 793-800; 2000.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1002/jlb.67.6.793

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.

HLA-B7 beta-pleated sheet-derived synthetic peptides are immunodominant T-cell epitopes regulating alloresponses.

We postulated that indirect recognition of MHC-derived peptides might modulate the alloresponse to donor antigen. In this study, we looked at the potential of two class I peptides derived from the αl and α2 regions of the DA RT1Aa molecule. Lew responder rats were immunized by varying concentrations of two 25mer peptides covering residues 56–81 and 96–120. The injections were under the footpad and were repeated on day 14. The thickness of the footpads was measured to control delayed-type hypersensitivity (DTH). The animals were sacrificed on day 16 and the splenocytes were tested in mixed lymphocyte culture as responders against DA stimulator cells and CAP third-party splenocytes. In addition, the phenotype of the cells was measured using flow cytometry with antibodies against CD4, CD8, CD5, MHC class II, CD25, CD14 and CD19. Peptide 96120 induced strong sensitization of the Lew recipient animals at concentrations of 200–500 μg (n = 4). The stimulation index was 2–3 times higher than that of untreated animals. Peptide 56-81 failed to induce sensitization at the concentrations used, but surprisingly induced a concentration-dependent immunosuppression that was highest at 400 μg (n = 4). In proliferation experiments responder Lew rats proliferated only to peptide 56–81 in vitro.

Rat MHC class I peptides are immunogenic

Recognition of HLA-derived peptides in transplant patients.

A series of peptides derived from the α1 and α2 regions of the HLA-B7 and HLA-A2 molecules was synthesized with an automatic peptide synthesizer using the FMOC (9-fluorenylmethoxycarbonyl) technique. Peptides were analyzed and purified by reversed-phase high pressure liquid chromatography (HPLC). Peptide purity was > 96%. The effect of B7 peptides on mixed lymphocyte cultures was tested in vivo. The alloresponse in the cultures with B7 peptides was strongly enhanced. The peptides that were most effective inhibited cytotoxic T-lymphocyte (CTL) cytolysis. The data show that the peptides are immunogenic and that they are recognised by both the direct and indirect pathways. Further, the mechanism of peptide recognition was studied. We coupled peptide B7 (residues 62–70 in HLA-B7) and peptide A2 (residues 62–70 in HLAB2) covalently to fluorescein isothiocyanate (FITC). B7-specific CTLs were incubated with these peptides at 37°C for 90 min and cell fluorescence measured by flow cytometry. The B7 peptide was bound by 60% of the CTLs whereas the A2 peptide, as a negative control, bound only 10%. The molecular size of the ligands to which the peptides bind are being characterized by immunoprecipitation.

Determination of HLA‐B7 T‐cell epitopes

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