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Role of the thymus in transplantation tolerance in miniature swine. I. Requirement of the thymus for rapid and stable induction of tolerance to class I-mismatched renal allografts.

Yamada K, Gianello PR, Ierino FL, Lorf T, Shimizu A, Meehan S, Colvin RB, Sachs DH - J. Exp. Med. (1997)

Bottom Line: Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25(+)) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti-donor CTL reactivity in vitro.Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25(+) cells and no anti-donor CTL response in vitro.These results indicate that the thymus is required for rapid and stable induction of tolerance.

View Article: PubMed Central - PubMed

Affiliation: Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 02129, USA.

ABSTRACT
The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25(+)) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti-donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25(+) cells and no anti-donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance.

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Schematic diagram of the origin of available homozygous  porcine MHC haplotypes. Partially inbred SLAaa, SLAcc, and SLAdd haplotypes were derived from the original founder miniature swine. Recombination events between the MHC class I and class II haplotypes have  been identified and maintained as homozygous, recombinant haplotypes  SLAff, SLAgg, SLAhh, SLAjj, and SLAkk.
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Figure 1: Schematic diagram of the origin of available homozygous porcine MHC haplotypes. Partially inbred SLAaa, SLAcc, and SLAdd haplotypes were derived from the original founder miniature swine. Recombination events between the MHC class I and class II haplotypes have been identified and maintained as homozygous, recombinant haplotypes SLAff, SLAgg, SLAhh, SLAjj, and SLAkk.

Mentions: Transplant donors and recipients were selected from our herd of partially inbred miniature swine at 5–7 mo of age. The immunogenetic characteristics of this herd and of the intra-MHC recombinant haplotypes available have been described previously (5–7). The haplotypes of miniature swine used in this study are shown schematically in Fig. 1. Recombinant swine lymphocyte antigen (SLA)gg (class Ic/IId) animals were used as kidney donors, and SLAdd (class Id/IId) animals were used as recipients to achieve a 2-haplotype class I mismatch. All recipients were tested for cell-mediated lympholysis (CML) reactivity to SLAgg targets before kidney transplantation, and demonstrated significant cytotoxic activity (>20% percent-specific lysis [PSL]).


Role of the thymus in transplantation tolerance in miniature swine. I. Requirement of the thymus for rapid and stable induction of tolerance to class I-mismatched renal allografts.

Yamada K, Gianello PR, Ierino FL, Lorf T, Shimizu A, Meehan S, Colvin RB, Sachs DH - J. Exp. Med. (1997)

Schematic diagram of the origin of available homozygous  porcine MHC haplotypes. Partially inbred SLAaa, SLAcc, and SLAdd haplotypes were derived from the original founder miniature swine. Recombination events between the MHC class I and class II haplotypes have  been identified and maintained as homozygous, recombinant haplotypes  SLAff, SLAgg, SLAhh, SLAjj, and SLAkk.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199031&req=5

Figure 1: Schematic diagram of the origin of available homozygous porcine MHC haplotypes. Partially inbred SLAaa, SLAcc, and SLAdd haplotypes were derived from the original founder miniature swine. Recombination events between the MHC class I and class II haplotypes have been identified and maintained as homozygous, recombinant haplotypes SLAff, SLAgg, SLAhh, SLAjj, and SLAkk.
Mentions: Transplant donors and recipients were selected from our herd of partially inbred miniature swine at 5–7 mo of age. The immunogenetic characteristics of this herd and of the intra-MHC recombinant haplotypes available have been described previously (5–7). The haplotypes of miniature swine used in this study are shown schematically in Fig. 1. Recombinant swine lymphocyte antigen (SLA)gg (class Ic/IId) animals were used as kidney donors, and SLAdd (class Id/IId) animals were used as recipients to achieve a 2-haplotype class I mismatch. All recipients were tested for cell-mediated lympholysis (CML) reactivity to SLAgg targets before kidney transplantation, and demonstrated significant cytotoxic activity (>20% percent-specific lysis [PSL]).

Bottom Line: Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25(+)) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti-donor CTL reactivity in vitro.Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25(+) cells and no anti-donor CTL response in vitro.These results indicate that the thymus is required for rapid and stable induction of tolerance.

View Article: PubMed Central - PubMed

Affiliation: Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 02129, USA.

ABSTRACT
The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25(+)) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti-donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25(+) cells and no anti-donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance.

Show MeSH
Related in: MedlinePlus