Rejection Responses to Allogeneic Hepatocytes by Reconstituted Scid Mice, Cd4 Ko, and Cd8 Ko Mice1,2

Bumgardner, Ginny L.; Gao, Donghong; Li, Jiashun; Baskin, Joseph H; Heininger, Marie; Orosz, Charles G.

doi:10.1097/00007890-200012270-00017

Cited by 47 publications

(104 citation statements)

References 37 publications

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“…We have demonstrated that this is due to the relative 'immunoresistance' of the CD8-dependent rejection pathway (3,4). In the current study, we show the important in vivo role of LFA-1 mediated signals on hepatocyteinitiated CD8 + T-cell-dependent alloimmunity.…”

Section: Discussionsupporting

confidence: 53%

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Wang

Gao

Lunsford

et al. 2003

American Journal of Transplantation

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Allogeneic hepatocytes elicit CD4-dependent and (CD4-independent) CD8 + T-cell-initiated graft rejection. The (CD4-independent) CD8 + T-cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4 + T-cell-dependent rejection responses. Consequently, successful immunoregulation of hepatocyte-initiated immune responses requires a strategy which regulates both CD4-dependent and CD8-dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4-and CD8-dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4-dependent hepatocyte rejection, but is ineffective for suppression of CD8-dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post-transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA-1 and CD40L-mediated signals. Targeting LFA-1 suppressed (CD4-independent) CD8 + T-cell-initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA-1-mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4-and CD8-dependent T-cell pathways available).

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Section: Discussionsupporting

confidence: 53%

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Wang

Gao

Lunsford

et al. 2003

American Journal of Transplantation

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“…Whether hepatic engraftment with PEPs results in temporary or long-term allogeneic chimerism or induces tolerance to other allografts, as has been reported in another stem cell transplant model (27), also requires further study. Our observation of allogeneic graft survival is especially intriguing, given that mature allogeneic hepatocytes are vigorously rejected via CD4 and CD8 (nonclassical) pathways when transplanted into the liver, (28,29). Even though the immunological mechanisms leading to graft persistence are not known, our finding that PEP engraftment occurs across a major MHC barrier is very encouraging for the use of allogeneic ES stem cells for treating human disease.…”

Section: Discussionmentioning

confidence: 97%

Correction of factor IX deficiency in mice by embryonic stem cells differentiated in vitro

Fair

Cairns

Lapaglia

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…H epatocellular allografts have previously been demonstrated to initiate both CD4 ϩ T cell-dependent and (CD4 ϩ T cell-independent) CD8 ϩ T cell-dependent pathways of allograft rejection (1)(2)(3)(4). The activity of the latter CD8-dependent rejection pathway can be demonstrated following transplantation of hepatocellular allografts into CD4 knockout (KO) 4 mice (1), CD4-depleted C57BL/6 mice (2), and CD8-reconstituted SCID mice (1,4).…”

mentioning

confidence: 99%

“…The activity of the latter CD8-dependent rejection pathway can be demonstrated following transplantation of hepatocellular allografts into CD4 knockout (KO) 4 mice (1), CD4-depleted C57BL/6 mice (2), and CD8-reconstituted SCID mice (1,4). The CD8-dependent pathway is of particular interest because it is resistant to immunosuppressive strategies that readily regulate CD4 ϩ T cell-dependent alloimmune responses (5)(6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

“…The CD8-dependent pathway of rejection occurs not only in response to hepatocellular allografts (1)(2)(3)(4), but also in response to intestinal allografts (10 -12), and, under particular experimental conditions, to skin allografts (9,13) and cardiac allografts (7,8). These studies consistently demonstrate that this pathway is resistant to immunoregulation with strategies that are very effective at suppressing CD4-dependent immune activation such as Rapamycin (14), Cyclosporine (15), anti-CD4 mAb (7,9,16), gallium nitrate (16), anti-CD154 mAb (7,9,11), combined treatment with donor-specific transfusion and anti-CD154 mAb (5,17), and CTLA4-Ig (6,9,10).…”

mentioning

confidence: 99%

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Targeting LFA-1 and CD154 Suppresses the In Vivo Activation and Development of Cytolytic (CD4-Independent) CD8+ T Cells

Lunsford

Koester

Eiring

et al. 2005

The Journal of Immunology

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Short-term immunotherapy targeting both LFA-1 and CD40/CD154 costimulation produces synergistic effects such that long-term allograft survival is achieved in the majority of recipients. This immunotherapeutic strategy has been reported to induce the development of CD4+ regulatory T cells. In the current study, the mechanisms by which this immunotherapeutic strategy prevents CD8+ T cell-dependent hepatocyte rejection in CD4 knockout mice were examined. Combined blockade of LFA-1 and CD40/CD154 costimulation did not influence the overall number or composition of inflammatory cells infiltrating the liver where transplanted hepatocytes engraft. Expression of T cell activation markers CD43, CD69, and adhesion molecule CD103 by liver-infiltrating cells was suppressed in treated mice with long-term hepatocellular allograft survival compared to liver-infiltrating cells of untreated rejector mice. Short-term immunotherapy with anti-LFA-1 and anti-CD154 mAb also abrogated the in vivo development of alloreactive CD8+ cytotoxic T cell effectors. Treated mice with long-term hepatocyte allograft survival did not reject hepatocellular allografts despite adoptive transfer of naive CD8+ T cells. Unexpectedly, treated mice with long-term hepatocellular allograft survival demonstrated prominent donor-reactive delayed-type hypersensitivity responses, which were increased in comparison to untreated hepatocyte rejectors. Collectively, these findings support the conclusion that short-term immunotherapy with anti-LFA-1 and anti-CD154 mAbs induces long-term survival of hepatocellular allografts by interfering with CD8+ T cell activation and development of CTL effector function. In addition, these recipients with long-term hepatocellular allograft acceptance show evidence of immunoregulation which is not due to immune deletion or ignorance and is associated with early development of a novel CD8+CD25high cell population in the liver.

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Rejection Responses to Allogeneic Hepatocytes by Reconstituted Scid Mice, Cd4 Ko, and Cd8 Ko Mice1,2

Cited by 47 publications

References 37 publications

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Targeting LFA-1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4-Dependent and CD8-Dependent Rejection

Correction of factor IX deficiency in mice by embryonic stem cells differentiated in vitro

Targeting LFA-1 and CD154 Suppresses the In Vivo Activation and Development of Cytolytic (CD4-Independent) CD8+ T Cells

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