Intensity of transplant chronic rejection correlates with level of graft-infiltrating regulatory cells

Semiletova, Natalya V.; Shen, Xiu-Da; Baibakov, Boris; Andakyan, Arthur

doi:10.1016/j.healun.2009.08.003

Cited by 9 publications

(6 citation statements)

References 19 publications

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“…Regulatory T cells (Treg) were first described as a subpopulation of circulating CD4 + T cells that express the interleukin-2 (IL-2) receptor a chain (CD25) and play a crucial role in maintaining self-tolerance. 1 Over the years, several additional functions of Treg cells in human and murine systems have been suggested, such as control of allergy, [2][3][4][5] limitation of chronic inflammation in various diseases, [6][7][8] induction of transplantation tolerance, [9][10][11] but also inhibition of the immune responses to tumours. [12][13][14] Horses, unlike other livestock animals, are particularly prone to allergic and autoimmune diseases and have infectious diseases and tumours related to those occurring in humans.…”

Section: Introductionmentioning

confidence: 99%

Equine CD4+ CD25high T cells exhibit regulatory activity by close contact and cytokine-dependent mechanisms in vitro

et al. 2011

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Summary Horses are particularly prone to allergic and autoimmune diseases, but little information about equine regulatory T cells (Treg) is currently available. The aim of this study therefore was to investigate the existence of CD4+ Treg cells in horses, determine their suppressive function as well as their mechanism of action. Freshly isolated peripheral blood mononuclear cells (PBMC) from healthy horses were examined for CD4, CD25 and forkhead box P3 (FoxP3) expression. We show that equine FoxP3 is expressed constitutively by a population of CD4+ CD25+ T cells, mainly in the CD4+ CD25high subpopulation. Proliferation of CD4+ CD25− sorted cells stimulated with irradiated allogenic PBMC was significantly suppressed in co‐culture with CD4+ CD25high sorted cells in a dose‐dependent manner. The mechanism of suppression by the CD4+ CD25high cell population is mediated by close contact as well as interleukin (IL)‐10 and transforming growth factor‐β1 (TGF‐β1) and probably other factors. In addition, we studied the in vitro induction of CD4+ Treg and their characteristics compared to those of freshly isolated CD4+ Treg cells. Upon stimulation with a combination of concanavalin A, TGF‐β1 and IL‐2, CD4+ CD25+ T cells which express FoxP3 and have suppressive capability were induced from CD4+ CD25− cells. The induced CD4+ CD25high express higher levels of IL‐10 and TGF‐β1 mRNA compared to the freshly isolated ones. Thus, in horses as in man, the circulating CD4+ CD25high subpopulation contains natural Treg cells and functional Treg can be induced in vitro upon appropriate stimulation. Our study provides the first evidence of the regulatory function of CD4+ CD25+ cells in horses and offers insights into ex vivo manipulation of Treg cells.

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Section: Introductionmentioning

confidence: 99%

Equine CD4+ CD25high T cells exhibit regulatory activity by close contact and cytokine-dependent mechanisms in vitro

et al. 2011

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“…Besides, intragraft regulatory T‐cells have also been associated with reduced alloresponsiveness and stable function in human kidney transplant recipients [21–23]. Chronically rejecting patients, on the other hand, exhibited significantly less FoxP3+ regulatory T‐cells [24,25]. In contrast, intragraft FoxP3 expression was found to correlate with interstitial fibrosis, acute rejection, and poor graft outcome in kidney transplant recipients [26].…”

Section: Discussionmentioning

confidence: 99%

Modified CD4+ T-cell response in recipients of old cardiac allografts

Denecke

Jurisch

et al. 2011

Transplant International

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Summary With an increasing demand, organs from elderly donors are more frequently utilized for transplantation. Herein, we analyzed the impact of donor age on CD4+ T‐cell responses with regard to regulatory and effector mechanisms. Young (3 months) BM12 recipients were engrafted with young or old (18 months) B6 cardiac allografts. Systemic CD4+ T‐cell responses and intragraft changes were monitored and compared to age‐matched syngenic transplant controls. While elderly, nonmanipulated hearts contained significantly elevated frequencies of donor‐derived leukocytes prior to transplantation, allograft survival was age‐independent. T‐cell activation, however, was delayed and associated with a compromised immune response in mixed lymphocyte cultures (MLR; P = 0.0002) early after transplantation (day 14). During the time course after transplantation, recipients of old grafts demonstrated an augmented immune response as shown by significantly higher frequencies of activated CD4+ T‐cells and a stronger in vitro alloreactivity (MLR; ELISPOT; P < 0.01). In parallel, frequencies of regulatory T‐cells had increased systemically and overall fewer CD4+ T‐cells were detected intragraft. Interestingly, changes in the CD4+ T‐cell response were not reflected by graft morphology. Of note, transplantation of young and old syngenic hearts did not show age‐related differences of the CD4+ T‐cells response suggesting that old grafts can recover from a period of short cold ischemia time. Our data suggest that donor age is associated with an augmented CD4+ T‐cells response which did not affect graft survival in our model. These findings contribute to a better understanding of the immune response following the engraftment of older donor organs.

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“…These lesions were shown by Singer et al [38] to be diminished in long-term graft-surviving ACI recipients of WF grafts compared with untreated and CsA-treated controls. In addition, the adoptive transfer of T cells conditioned with allochimeric class I MHC into secondary recipients also resulted in decreased evidence of chronic rejection, which suggests the role of antigen-specific T regulatory cells in attenuating detrimental graft injury [61].…”

Section: Molecular and Cellular Pathways Involved In Inhibition Of Chmentioning

confidence: 97%

Molecular and cellular pathways involved in the therapeutic functions of MHC molecules; a novel approach for mitigation of chronic rejection

Skelton¹,

Kloc²,

Ghobrial³

2011

OJI

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The mutated major histocompatibility complex (MHC) class I that contains donor-type epitopes displayed on recipient-type molecule was show- n to inhibit acute and chronic rejection and in-duce indefinite survival of heterotopic cardiac allografts when administered in combination with a sub-therapeutic dose of cyclosporine (CsA) in a rat transplantation model. To eluci-date the molecular pathways involved in the immunosuppressive effects of the mutated MHC molecule, we analyzedgene and protein expres-sion profile during early and late phase follow-ing post-transplantation. Cytoskeletal structure analysis and expression status of Rho GTPase proteins, vacuolar transport and cytoskeleton regulatory pathways involved in immune re-sponse in T and dendritic cells demonstrated the novel mechanism for the abrogation of chronic rejection. Our studies confirm a new role of Rho GTPase pathway in the modification of T cell motility and infiltration of the graft. We discuss these results within the framework of the most recent literature on MHC and molecu-lar machinery controlling T cell functions and dendritic cell antigen presentation

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Intensity of transplant chronic rejection correlates with level of graft-infiltrating regulatory cells

Cited by 9 publications

References 19 publications

Equine CD4+ CD25high T cells exhibit regulatory activity by close contact and cytokine-dependent mechanisms in vitro

Equine CD4+ CD25high T cells exhibit regulatory activity by close contact and cytokine-dependent mechanisms in vitro

Modified CD4+ T-cell response in recipients of old cardiac allografts

Molecular and cellular pathways involved in the therapeutic functions of MHC molecules; a novel approach for mitigation of chronic rejection

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