Cd4-Positive Helper T Lymphocytes Mediate Mouse Cardiac Allograft Rejection Independent of Donor Alloantigen Specific Cytotoxic T Lymphocytes

Bishop, D. Keith; Chan, Stephanie; Li, Wenhua; Ensley, Rebecca; Xu, Shixuan; Eichwald, E. J.

doi:10.1097/00007890-199310000-00023

Cited by 70 publications

(40 citation statements)

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“…Other approaches have been used to examine this question, but they have their own limitations. For example, CD8-depleted mice clearly reject vascularized cardiac allografts (30)(31)(32)(33). This setting, however, differs from the bm12/B6 combination in potentially important ways.…”

Section: Discussionmentioning

confidence: 99%

Allograft Rejection in a New Allospecific CD4+ TCR Transgenic Mouse

Sayegh

Hancock

et al. 2003

American Journal of Transplantation

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The application of TCR transgenic mice to transplantation immunology is hampered by the limited lines available. Recently, we reported CD4 + T cell receptor (TCR) transgenic mice specific for I-A bm12 expressed on B6.C.H-2 bm12 mice. Here, we characterized rejection of skin and vascularized cardiac allografts in these mice, which we term ABM (for anti-bm12). In vivo proliferative experiments reveal that all CD4 T cells in ABM mice react to bm12 antigens. Surprisingly, while ABM mice have accelerated (compared to B6 recipients) rejection of bm12 skin allografts, they, like B6 recipients, fail to acutely reject bm12 cardiac allografts. This is not due to lack of immunogenicity of bm12 hearts, as these grafts are acutely rejected by primed ABM recipients, although not by primed B6 recipients. Lastly, long-term surviving bm12 grafts in ABM recipients are relatively free from chronic rejection (compared with B6 recipients), which may be due to skewing of the CD4 repertoire towards direct alloreactivity, and consequent lack of CD4 mediated indirect allorecognition as evidenced by the lack of IgG deposition in those grafts. The results indicate that a complex interplay between responder frequency, priming and repertoire dictates the occurrence, or lack thereof, of acute and chronic rejection.

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Section: Discussionmentioning

confidence: 99%

Allograft Rejection in a New Allospecific CD4+ TCR Transgenic Mouse

Sayegh

Hancock

et al. 2003

American Journal of Transplantation

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“…There have been many studies reported in the literature regarding the T-cell subsets that mediate allograft rejection and whether they function through the direct or indirect pathway (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). These studies have provided different results depending on the tissues that have been transplanted, the models that have been used, and the strain combinations that have been studied.…”

Section: Introductionmentioning

confidence: 99%

Further Analysis of the T-Cell Subsets and Pathways of Murine Cardiac Allograft Rejection

Yamada

Laufer

Gerth

et al. 2003

American Journal of Transplantation

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The present study examined the role of CD4 π and CD8 π T cells in cardiac allograft rejection when either the direct or indirect pathway was eliminated for the CD4 π portion of the response. To study the pathways in vivo, we used genetically altered mouse strains that lack class II antigens as either the donors or recipients for cardiac transplantation. In contrast to earlier published studies, which used different strain combinations, we found that either CD4-or CD8-depletion prolonged cardiac allograft survival moderately, but not indefinitely, in an MHC-mismatched, minor-matched combination. When the CD4 π indirect pathway was eliminated, rapid graft rejection occurred when both T-cell subsets were present and when either CD4 π or CD8 π T cells were depleted. When the CD4 π direct pathway was eliminated, rapid graft rejection occurred when both T-cell subsets were present, there was slow rejection when CD4 π T cells were eliminated, and no rejection was seen for more than 100 days when CD8 π T cells were eliminated. However, the long-surviving allografts on the recipients with only CD4 π cells and an indirect pathway did show evidence of chronic vasculopathy. Thus, either CD4 π or CD8 π T cells can mediate acute cardiac allograft rejection in these experiments when both pathways are available. In addition, CD4 π T cells can provide help for acute rejection through either the direct or indirect pathway. Finally, recipients who have only CD4π cells and an indirect pathway do not demonstrate acute rejection, but do show evidence of chronic rejection.

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“…The fact that IL-4 producing Th2 were rare comes as no surprise since we have previously reported that rejection in this model is characterized by a CD8+ Th1 dominated response (13,(26)(27)(28). Depletion of CD8+ cells reduces IFNγ production and allows Th2 responses to emerge (13,27,28).…”

Section: Impact Of P21 On In Vivo T Cell Responses Following Transplamentioning

confidence: 85%

“…We have previously reported that CD8+ cells represent a major source of IFNγ in this model and depleting CD8+ cells reduces IFNγ production and induces Th2 responses (13,27). Thus, depleting p21−/− vs. WT allograft recipients of CD8+ cells allowed us to investigate the impact of p21 on in vivo Th2 priming and CD4+ T cell mediated rejection (28). While depleting recipients of CD8+ cells did induce measurable Th2 responses in both groups, there was no difference in the level of Th2 priming in p21−/− vs. WT recipients.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

Welling

Csencsits

et al. 2008

Surgery

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Background-The cyclin-dependent kinase (cdk) inhibitor p21 inhibits cellular proliferation of many cell types, including T cells. However, autoimmune models have yielded conflicting results regarding the role of cdk inhibitors and T cell function. The role of p21 in T cell function following transplantation has not been directly investigated. We hypothesized that p21 plays an important role in alloantigen-driven responses in vitro in mixed lymphocyte cultures (MLC) and in vivo using the heterotopic murine cardiac allograft model.

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Cd4-Positive Helper T Lymphocytes Mediate Mouse Cardiac Allograft Rejection Independent of Donor Alloantigen Specific Cytotoxic T Lymphocytes

Cited by 70 publications

References 0 publications

Allograft Rejection in a New Allospecific CD4+ TCR Transgenic Mouse

Allograft Rejection in a New Allospecific CD4+ TCR Transgenic Mouse

Further Analysis of the T-Cell Subsets and Pathways of Murine Cardiac Allograft Rejection

Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

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