Transplantation in miniature swine: analysis of graft-infiltrating lymphocytes provides evidence for local suppression

Rosengard, Bruce R.; Kortz, Eric O.; Guzzetta, Philip C.; Sundt, Thoralf M.; Ojikutu, Christina A.; Alexander, Richard B.; Sachs, David H.

doi:10.1016/0198-8859(90)90012-e

Cited by 17 publications

(10 citation statements)

References 8 publications

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“…Although we have provided no direct evidence for an increase, or even the presence, of regulatory T cells in this study, our results may be explained by one of the following hypotheses, which are supported by our previous experimental data: 1) that tolerance in this model is dependent on the presence of regulatory T cells (Tregs), both in the graft (17) and in peripheral lymphoid compartments (10,18); 2) that alloreactive T cell precursors are present in tolerant animals (19), but are inhibited from activation by Tregs (10,20); and 3) based on other animal models, that peripheral Tregs decrease progressively in number, potency, and/or affinity after the donor kidney is removed (21–23). …”

Section: Discussionsupporting

confidence: 48%

Tolerogenicity of Donor Major Histocompatibility Complex–Matched Skin Grafts in Previously Tolerant Massachusetts General Hospital Miniature Swine

et al. 2012

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Background Long-term tolerance (LTT) of class I disparate renal allografts in miniature swine can be induced by a short-course of cyclosporine and persists for 3 to 4 months after grafts are removed. Donor class I peptide immunization 6 weeks after graftectomy of tolerated kidneys leads to sensitization but, donor skin grafts do not. Here, we tested the hypothesis that skin grafts prevent rejection following simultaneous peptide administration and skin grafting. Methods Miniature swine underwent bilateral nephrectomy and class I mismatched renal transplantation with a 12-day course of CyA to induce LTT. Tolerated allografts were then replaced with recipient-matched kidneys, and animals were challenged with simultaneous donor-type skin grafts and peptide. Six-weeks later, second donor-matched kidneys were transplanted without immunosuppression and immune responses were characterized. Results Animals treated only with peptide (n=2) rejected subsequent renal transplants in 3–5 days with strong in-vitro anti-donor responses. Of five recipients of skin-plus-peptide, two accepted kidneys long-term, one demonstrated modestly prolonged survival (11 days) and two rejected rapidly (5–7 days). The two long-term acceptors maintained donor-specific hyporesponsiveness in vitro. Conclusions Sensitization by class I peptide in previously tolerant swine could be prevented by simultaneous class I skin grafts. These data suggest that skin grafts may actually augment rather than abrogate down-regulation in some cases. A mechanistic hypothesis for this surprising result is that recognition of class I antigens via the direct rather than indirect pathway of antigen presentation promotes tolerance by expanding regulatory T cells.

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Section: Discussionsupporting

confidence: 48%

Tolerogenicity of Donor Major Histocompatibility Complex–Matched Skin Grafts in Previously Tolerant Massachusetts General Hospital Miniature Swine

et al. 2012

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“…MHC class II-matched kidney (but not heart) allografts in partially inbred miniature swine given a short course of post-transplant cyclosporine treatment are accepted indefinitely (29) and combined kidney-heart allografts are also accepted. Furthermore, the pro-tolerogenic effect of the kidney was abolished by prior x-irradiation of the donor, suggesting a radiosensitive kidney passenger leukocyte was responsible (27).…”

Section: Discussionmentioning

confidence: 99%

Pretransplant Immune Regulation Predicts Allograft Outcome

Jankowska‐Gan

Sheka²,

Sollinger³

et al. 2012

Transplantation

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Background Tolerance to non-inherited maternal antigens (NIMA) has provided clinical advantage when kidney transplants are exchanged between siblings, but not when mother herself is the donor. This paradox prompted us to revisit the “two-way” hypothesis of transplant tolerance—that the immune status of both the organ recipient and the organ donor critically influences allograft outcome. Methods We obtained PBMC from 29 living donor-recipient pairs prior to transplant and used the trans-vivo DTH assay to measure immune regulation in both the recipient anti-donor and donor anti-recipient directions. Results We found pre-existing bidirectional regulation in all HLA-identical sibling pairs tested (7/7), and half (9/18) the HLA haploidentical pairs. No significant regulation was found in 4 control living unrelated (LUR) and 2 HLA haploidentical living-related (LR) donor recipient pairs, while unidirectional regulation was found in the remaining 7 haploidentical pairs. Of the 9 HLA haploidentical transplants with unidirectional or no pre-transplant regulation, 7 had an acute rejection episode, and 4 of these experienced graft loss. In contrast, of the 9 HLA haploidentical transplants with bidirectional regulation, only 1 had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years post-transplant. Significantly (p<0.05) lower mean sCr values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (p<0.005) and 36 months (p<0.0001). Conclusions Contrary to the belief that only the recipient’s immune status matters, the data indicate that pre-transplant immune status of both donor and recipient influence post transplant outcome.

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“…The role of local regulation in peripheral T cell tolerance has been further strengthened by in vitro experiments comparing the functional properties of PBL and GITC from tolerant animals. Peripheral cells from tolerant animals could generate antidonor lymphocytotoxicity with appropriate stimulation, whereas under similar conditions, GITC from the same animal displayed no antidonor CTL reactivity (11). These findings suggested that GITC included cell subsets able to down-regulate T cell activity, whereas PBL lacked such regulatory properties.…”

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confidence: 58%

Persistence of Dominant T Cell Clones in Accepted Solid Organ Transplants

Baron

McMorrow

Sachs

et al. 2001

The Journal of Immunology

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Donor/recipient MHC class II matching is beneficial to the survival of allogeneic kidneys in humans and swine. In the latter, tolerance to class I-disparate grafts can be induced by a short course of immunosuppression, a peripheral mechanism that implicates regulatory T cells. Absence of treatment will lead to prompt rejection. Rejected grafts are infiltrated by dominant alloaggressive T cells, whereas there is still speculation on the specificity and function of T cells invading accepted tissues. To characterize the TCR repertoire of graft-infiltrating T cells (GITC) in accepted kidneys, we have used the RT-PCR-based spectratyping technique to assess the length polymorphism of the porcine TCRβ chain complementary-determining region 3 (CDR3). Results show that T cells infiltrating accepted kidneys (n = 5) express a restricted polymorphism of the CDR3 length, whereas PBL from the same animal have the polymorphic distribution of CDR3 lengths found in naive animals; that the skewed Vβ repertoire in accepted grafts involved distinct Vβ subfamilies in otherwise MHC-identical recipient animals; that GITC clonal dominance is not caused by immunosuppression because a second kidney, accepted without drug treatment, exhibits the same TCR Vβ CDR3 profiles than those detected in the first graft; and that intragraft clonal dominance intensifies with time, indicating progressive preeminence of nonaggressive GITC clones. Collectively, these data represent the first example, in a preclinical model, of the emergence of nonaggressive intragraft clones, which may be involved in the induction/maintenance of local tolerance to allogeneic tissues.

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Transplantation in miniature swine: analysis of graft-infiltrating lymphocytes provides evidence for local suppression

Cited by 17 publications

References 8 publications

Tolerogenicity of Donor Major Histocompatibility Complex–Matched Skin Grafts in Previously Tolerant Massachusetts General Hospital Miniature Swine

Tolerogenicity of Donor Major Histocompatibility Complex–Matched Skin Grafts in Previously Tolerant Massachusetts General Hospital Miniature Swine

Pretransplant Immune Regulation Predicts Allograft Outcome

Persistence of Dominant T Cell Clones in Accepted Solid Organ Transplants

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