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1.
Am J Transplant ; 6(7): 1541-50, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16827854

ABSTRACT

Exosomes are MHC-bearing vesicles secreted by a wide array of cells. We have previously shown that donor-haplotype exosomes from bone marrow dendritic cells (DCs) injected before transplantation significantly prolong heart allograft survival in congenic and fully MHC-mismatched Lewis rats. Here we show that donor exosomes administered after transplantation are similarly able to prolong allograft survival, however, without inducing tolerance. We therefore tested the effect of exosomes combined with short-term LF 15-0195 (LF) treatment, which blocks the maturation of DCs, so that donor-MHC antigens from exosomes could be presented in a more tolerogenic environment. LF treatment does not preclude the development of a strong antidonor cellular response, and while LF, but not exosome, treatment inhibits the antidonor humoral response and decreases leukocyte graft infiltration, allografts from LF-treated recipients were either acutely or strongly chronically rejected. Interestingly, when combined with LF treatment, exosomes induced a donor-specific allograft tolerance characterized by a strong inhibition of the antidonor proliferative response. This donor-specific tolerance was transferable to naïve allograft recipients. Moreover, exosomes/LF treatment prevented or considerably delayed the appearance of chronic rejection. These results suggest that under LF treatment, presentation of donor-MHC antigens (from exosomes) can induce regulatory responses that are able to modulate allograft rejection and to induce donor-specific allograft tolerance.


Subject(s)
Dendritic Cells/cytology , Dendritic Cells/immunology , Exocytosis , Heart Transplantation/immunology , Histocompatibility Antigens/immunology , Immune Tolerance/immunology , Immunosuppression Therapy , Animals , Chronic Disease , Graft Rejection/immunology , Graft Rejection/prevention & control , Graft Survival/drug effects , Graft Survival/immunology , Guanidines/pharmacology , Immune Tolerance/drug effects , Intracellular Membranes/immunology , Isoantibodies/biosynthesis , Isoantibodies/immunology , Male , Models, Animal , Rats , Time Factors , Tissue Donors , Transplantation, Homologous
2.
Eur J Immunol ; 31(5): 1333-9, 2001 May.
Article in English | MEDLINE | ID: mdl-11465090

ABSTRACT

Pre-graft priming of heart allograft recipients with donor strain blood induces tolerance in 100% of adult rats in the congenic LEW.1W to LEW.1A combination. This tolerant state is specific for donor MHC antigens as third-party blood transfusions fail to induce tolerance, and third-party skin grafts are promptly rejected by tolerant graft recipients. In this study we have characterized the immunodominant donor (RT1u) class I and II allogenic peptides which elicit an in vitro proliferative response to splenocytes from recipients (RT1a) undergoing acute rejection or tolerant to a LEW.1A cardiac allograft. Paradoxically, splenocytes from tolerant animals responded more vigorously to a broader set of donor peptides than splenocytes from rejecting animals. In addition, several of these peptides were observed to be stimulatory only for tolerant splenocytes. These findings suggest that regulatory cells may be involved in tolerance induction or maintenance and are selected by specific motifs, which could be utilized for manipulating the immune system of graft recipients.


Subject(s)
Graft Rejection/immunology , Heart Transplantation/immunology , Histocompatibility Antigens/immunology , Immunodominant Epitopes/immunology , Major Histocompatibility Complex/immunology , Transplantation Tolerance/immunology , Amino Acid Sequence , Animals , Cell Division , Histocompatibility Antigens/chemistry , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/immunology , Lymphocyte Activation , Male , Molecular Sequence Data , Rats , Rats, Inbred Lew , Spleen/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Transplantation, Homologous/immunology
3.
J Immunol ; 165(1): 96-101, 2000 Jul 01.
Article in English | MEDLINE | ID: mdl-10861040

ABSTRACT

Donor-specific allograft tolerance can be induced in the adult rat by pregraft donor-specific blood transfusion (DST). This tolerance appeared to be mediated by regulatory cells and to the production of the suppressive cytokine TGF-beta1. A potential immunoregulatory CD8+ clone bearing a Vbeta18-Dbeta1-Jbeta2.7 TCR gene rearrangement was previously identified in DST-treated recipients. To assess the functional role of this T cell clone in the induction of tolerance by DST, we have vaccinated DST-treated recipients with a plasmid construct encoding for the Vbeta18-Dbeta1-Jbeta2.7 TCR beta-chain. DST-induced allograft tolerance was abolished by anti-TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination in six of seven recipients, whereas vaccination with the vector alone, or with the construct encoding a TCR Vbeta13 beta-chain, had no effect. However, the transcript number of the Vbeta18-Dbeta1-Jbeta2.7 chain was unchanged in allografts from vaccinated DST-treated rats, suggesting that this clone was not depleted by vaccination, but rather was altered in its function. Moreover, TCR Vbeta18-Dbeta1-Jbeta2.7 DNA vaccination restored the anti-donor alloantibody production, partially restore the capacity of spleen cells from tolerized recipients to proliferate in vitro against donor cells, and decreased the inhibitory effect of TGF-beta1, seen in DST-treated recipients, in spleen cells from vaccinated DST-treated ones. This study strongly suggests that this CD8+ TCR Vbeta18-Dbeta1-Jbeta2.7 T cell clone has an effective immunoregulatory function in allograft tolerance induced by DST.


Subject(s)
Blood Transfusion , CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Genes, T-Cell Receptor beta/immunology , Heart Transplantation/immunology , Immune Tolerance , Vaccines, DNA/immunology , Animals , Clonal Deletion/genetics , Clone Cells , Cytokines/biosynthesis , Cytokines/genetics , Cytomegalovirus/genetics , Cytomegalovirus/immunology , Epitopes, T-Lymphocyte/genetics , Graft Rejection/genetics , Graft Rejection/immunology , Immune Tolerance/genetics , Immunoglobulin G/biosynthesis , Injections, Intramuscular , Isoantibodies/biosynthesis , Male , RNA, Messenger/biosynthesis , Rats , Rats, Inbred Lew , Spleen/cytology , Spleen/immunology , Transplantation, Heterotopic , Vaccines, DNA/administration & dosage , Vaccines, DNA/genetics , Viral Vaccines/administration & dosage , Viral Vaccines/genetics , Viral Vaccines/immunology
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