Improved technique of heart transplantation in rats

Ono, Keiji; Lindsey, Edward S.

doi:10.1097/00007890-196909000-00022

Cited by 305 publications

(340 citation statements)

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“…Heterotopic heart grafts were performed using the Ono and Lindsey technique. 35 Graft function was evaluated by daily palpation through the abdominal wall. Rejection was defined as total cessation of cardiac beating and was confirmed by direct examination following laparotomy.…”

Section: Animals and Heart Transplantationmentioning

confidence: 99%

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

et al. 2004

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Elevated expression of heme oxygenase-1 (HO-1), an intracellular enzyme that degrades heme into carbon monoxide (CO), biliverdine and free iron, has anti-inflammatory and antiapoptotic effects in diverse models. Here, we analyzed the effects of specific overexpression of HO-1 following adenovirus-mediated (AdHO-1) gene transfer in an acute cardiac allograft rejection model. The intragraft (i.g.) injection of AdHO-1 into cardiac allografts, as well as intramuscular (i.m.) or intravenous (i.v.) administration, prolonged allograft survival with, respectively, 13.3, 62.5 and 80% of the grafts surviving long term (4100 days), whereas control grafts were rejected with acute kinetics. HO-1 overexpression was associated with inhibited allogeneic responses in MLRs using graft-infiltrating leukocytes and splenocytes, but not with lymph node cells. The inhibition of splenocyte proliferation was mediated by soluble factors and was dependent on the presence of APCs, since purified T cells proliferated normally. i.v. but not i.g. AdHO-1 administration decreased the number of graft-infiltrating leukocytes, cytokine mRNA accumulation and apoptosis in transplanted hearts, whereas i.v. and i.g. AdHO-1 did not modify normal immune responses against cognate antigens, indicating that there was no general immunosuppression. These results indicate that HO-1 overexpression prolongs the survival of vascularized allografts by promoting tolerogenic mechanisms acting on allogeneic cellular immune responses.

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Section: Animals and Heart Transplantationmentioning

confidence: 99%

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

et al. 2004

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“…Intra-abdominal heterotopic cardiac grafting was performed using a modification of the technique described by Ono and Lindsey (20). Briefly, the donor animals were anesthetized with sodium pentobarbital (50 mg/kg intraperitoneally).…”

Section: Heterotopic Cardiac Graftsmentioning

confidence: 99%

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

Barten

Gelder

Gummert

et al. 2002

American Journal of Transplantation

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The primary mechanism of action in vivo of mycophenolate mofetil (MMF) is believed to be inhibition of lymphocyte proliferation. We used novel assays of lymphocyte functions (pharmacodynamics, PD) in whole blood collected from rat heart allograft recipients treated with MMF to investigate the mechanisms of action of the active metabolite of MMF, mycophenolate acid (MPA) in vivo. Allograft recipients were treated orally once daily with 3 different doses of MMF. Seven days after transplantation, blood was collected 24 h after the penultimate dose and several timepoints after the last dose, after which grafts were removed for microscopic grading of rejection. Lymphocytes in whole blood samples were mitogen stimulated through calcium-dependent and -independent signaling pathways. Inhibition of PD was measured by lymphocyte proliferation and expression of several surface antigens on T cells, and was calculated as area under the time-inhibition of immune function effect curve (AUE 0ª24 h ). We found that inhibition of lymphocyte proliferation and antigen expression by MPA correlated highly with MMF-dose, MPA level and with the histologic severities of graft rejection (p ∞0.05). In summary, MPA suppressed lymphocyte proliferation and expression of T-cell surface antigens in whole blood collected from MMF-treated allograft recipients, thus demonstrating the multiple mechanisms of suppression of rejection on peripheral blood T cells after MMF treatment.

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“…LEW.1 W or BN heart grafts were implanted heterotypically onto the LEW.1A recipient abdominal aorta and vena cava by using standard microsurgical techniques [55]. The graft was monitored by daily abdominal palpation and rejection was defined as complete cessation of heartbeat.…”

Section: Methodsmentioning

confidence: 99%

Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

et al. 2006

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Donor-specific heart allograft acceptance can be induced in the MHC-mismatched LEW.1 W to LEW.1A rat by donor-specific transfusions. Whereas the induction phase of tolerance has been studied in detail, its maintenance remained poorly understood. Here, we performed a side-by-side comparison of CD25 + and CD25 -splenic T cells of 100-day tolerant rats. Administration of CD25 -T cells from tolerant rats to sublethally irradiated recipients transferred long-term graft survival. These CD25 -T cells displayed a decreased donor-specific response in the mixed lymphocyte reaction and presented suppressive activity. These CD25 -T cells accumulated IFN-c, IL-10 and Foxp3 transcripts. The in vitro suppressive activity of CD25 -T cells required both cell contact and soluble factors (IL-10 and IFN-c). The CD25 + T cells from tolerant rats did not show any modification of their regulatory properties. We show that splenic CD25 -T cells of tolerant rats contribute to the maintenance of tolerance following the transplantation. Our data show that regulatory T cells are not restricted to the CD4 + CD25 + T cell subset and provide new insights on the mechanisms of tolerance to allograft following donor cell priming. IntroductionInduction of specific tolerance for donor antigens (see [1] for review) is one of the most actively explored fields in transplantation immunology. Donor-specific blood transfusion (DST) is a clinically and experimentally proven method to induce hyporesponsiveness and does not necessarily require additional immunotherapy [2][3][4][5][6]. However, the use of DST clinically has become less popular with the advent of calcineurin inhibitors and because a clear understanding of the mechanisms involved had remained elusive [4,6].In adult rats, long-term survival of MHC-incompatible vascularized allografts (heart or kidney) can be obtained by priming the recipients with donor blood cells [7,8]. We and others have shown that inhibition of early allograft rejection by DST mostly affects helper T cell functions [9][10][11] and requires intact resident dendritic cells at the time of transplantation [12]. Early production of and differentiation of CD8 + clonal regulatory cells [14][15][16] are also involved. DST treatment results in a complex state where symptoms of chronic graft rejection coexist [17] with mechanisms controlling the host acute anti-donor immune response. Long-term recipients accept a donor-derived skin graft whereas a third-party graft is rejected [17]. Moreover, the spleen [18], and possibly the graft itself [19], * These authors contributed equally to this paper. ** These authors contributed equally to this paper. harbors donor-specific regulatory T cells able to protect naive recipients from allogeneic heart rejection. Therefore, the immunological status of allograft recipients following DST pre-conditioning provides another example of the differentiation of regulatory cells described in mice [20][21][22][23] or in rats [18,24] following different "tolerance" induction maneuvers (see [25] for review)...

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Improved technique of heart transplantation in rats

Cited by 305 publications

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Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

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Improved technique of heart transplantation in rats

Cited by 305 publications

References 0 publications

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

Development of CD25– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

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Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival