CD4+ T-cell subsets and cytokines involved in peripheral tolerance

Weigle, William O.; Romball, Carole G.

doi:10.1016/s0167-5699(97)01151-1

Cited by 32 publications

(16 citation statements)

References 30 publications

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“…It is only at the mature stage that DC express the full complement of co-stimulatory molecules, adhesion molecules and antigen-presenting MHC molecules required for productive T cell activation [3][4][5][6][7][8]. Understanding the signals driving maturation of antigen-presenting DC may explain why purified protein antigens are prone to induce peripheral tolerance rather than immunity [9] and why addition of bacterial products such as LPS facilitates productive adoptive immune responses [10].…”

Section: Introductionmentioning

confidence: 99%

Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells

et al. 1998

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Bacterial DNA and immunostimulatory (i.s.) synthetic CpG-oligodeoxynucleotides (ODN) act as adjuvants for Th1 responses and cytotoxic T cell responses to proteinaceous antigens. Dendritic cells (DC) can be referred to as "nature's adjuvant" since they display the unique capacity to sensitize naive T cells. Here, we demonstrate that bacterial DNA or i.s. CpG-ODN cause simultaneous maturation of immature DC and activation of mature DC to produce cytokines. These events are associated with the acquisition of professional antigen-presenting cell (APC) function. Unfractionated murine bone marrow-derived DC and FACS-fractionated MHC class IIlow (termed immature DC) or MHC class IIhigh populations (termed mature DC) were stimulated with bacterial DNA or i.s. CpG-ODN. Similar to lipopolysaccharide, i.s. CpG-ODN caused up-regulation of MHC class II, CD40 and CD86, but not CD80 on immature and mature DC. In parallel both DC subsets were activated to produce large amounts of IL-12, IL-6 and TNF-alpha. CpG-ODN-activated DC displayed professional APC function in allogeneic mixed lymphocyte reaction and in staphylococcal enterotoxin B-driven naive T cell responses. We interpret these findings to mean that bacterial DNA and i.s. CpG-ODN cause maturation (first step) and activation (second step) of DC to bring about conversion of immature DC into professional APC.

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Section: Introductionmentioning

confidence: 99%

Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells

et al. 1998

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Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] Based on results of our previous studies [5][6][7][8] and other reports from the literature, 9,10 differential activation of type 2 cytokine-producing effector cells within the allograft correlates with its long-term survival. However, several studies [1][2][3][4] have suggested that this hypothesis may be an oversimplification and may not be applicable to the transplant setting. In addition, other studies have shown that increased expression of type 2 cytokines alone did not significantly prolong the survival of pancreatic islets in interleukin (IL) 2 gene knockout mice 11 or of heart transplants in anti-CD8 monoclonal antibody-treated rats 12 , and inhibition of both type 1 and type 2 cytokine pathways using CTLA4Ig and CD40 ligand monoclonal antibody treatment resulted in heart allograft survival and tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

“…A number of both animal and human studies have suggested that development of type 1 or type 2 cytokine-producing lymphocyte populations may influence the development of graft rejection or graft acceptance, respectively. [1][2][3][4][5][6][7][8] This paradigm remains controversial, especially as it relates to clinical transplantation, but our data demonstrate that under certain conditions, this model may be applicable using PBMCs from OLT recipients.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of Immunologic Status of Liver Transplant Recipients by Peripheral Blood Mononuclear Cells in Response to Stimulation by Donor Alloantigen

Chen¹,

McKenna²,

Yoshida³

et al. 1999

Annals of Surgery

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ObjectiveTo determine whether there is a role for assessing peripheral blood mononuclear cell (PBMC) cytokine patterns as a means of measuring the immunologic and clinical status of liver transplant recipients. Summary Background DataThe role of assessing cytokine patterns in the prediction of clinical graft rejection or acceptance remains unclear. The purpose of this study was to examine the cytokine profiles of PBMC stimulated in vitro with donor alloantigen and to correlate prospectively the data with clinical assessment of graft status in orthotopic liver transplant (OLT) recipients. MethodsPBMCs from OLT recipients were examined for proliferation and cytokine mRNA expression after stimulation by donor alloantigen, third-party alloantigen, or phytohemagglutinin (PHA). mRNA extracted from PBMC was amplified by reverse transcriptase-polymerase chain reaction with oligospecific primer pairs for interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN) ␥, tumor necrosis factor (TNF) ␣ and transforming growth factor (TGF) ␤. Results were prospectively correlated with each patient's allograft status. ResultsIncreased IL-4 and TGF-␤ and decreased IL-2, IFN␥, and TNF-␣ mRNA expression by PBMCs in response to donor alloantigen stimulation predicted immunologic graft stability over a minimum 60-day interval compared with mRNA expression of PBMCs from patients with established rejection or those who experienced a rejection episode within a 30-day period (p Ͻ 0.05). Stimulation of recipient PBMCs with thirdparty alloantigens or PHA yielded similar but less specific results. PBMC proliferation to varying antigenic stimulation did not correlate with clinical graft status, nor did cytokine production by unstimulated PBMC. ConclusionsProspective assessment of cytokine expression by PBMC from OLT recipients in response to stimulation by donor alloantigen is helpful for predicting the clinical status of the allograft and may be useful in the development of more precise immunologic monitoring protocols.Current immunosuppressive agents have allowed for marked improvements in the results of short-and longterm outcomes in clinical transplantation, but their use is associated with risks of opportunistic infections, malignancy, and other metabolic complications. Immunosuppression currently relies on the empirical use of these nonspecific immunosuppressive agents. Further, precise immunologic monitoring to determine the appropriate dose of drugs is not yet available. Studies examining methods to optimize the administration of immunosuppression are of significant interest, as are studies examining potential mechanisms involved in the induction of allograft hyporesponsiveness.

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“…In fact, the suggestion by us and others that tolerance results from the bypass of cytokinemediated signals has considerable experimental support. (7)(8)(9)(10)(11)(12)(13)(14)(15)(16) Previously, it has been demonstrated that bacterial lipopolysaccharide (LPS) interferes with the induction of tolerance, (7)(8)(9)14) likely through the activation of cytokines (reviewed in ref. 13).…”

Section: Introductionmentioning

confidence: 99%

Cytokines in the Induction and Circumvention of Peripheral Tolerance

Romball¹,

Weigle²

1999

Journal of Interferon & Cytokine Research

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Injection of deaggregated (monomeric) human gamma globulin (DHGG) into mice induces a state of immunological tolerance to subsequent challenge with immunogenic forms of HGG. Tolerance was shown to be induced in both the Th1 and Th2 CD4+ subsets. These mice fail to demonstrate antibody production, T cell proliferation, cytokine release, or T cell helper function. On the other hand, simultaneous injection of lipopolysaccharide (LPS) as well as interleukin-1 (IL-1) was capable of interfering with the induction of tolerance to DHGG. The purpose of the present study is to extend these investigations to determination of the cellular mechanisms responsible for the interference of tolerance induction in both CD4+ T cell subsets. It was demonstrated that LPS and IL-1 have differential effects on the induction of tolerance in the CD4+ subsets. As evidenced by immunoglobulin G (IgG) subclass, T helper cell function, and lymphokine secretion, coinjection of LPS with tolerogen interfered with the induction of tolerance in both subsets, whereas IL-1 interfered with the induction of tolerance exclusively in the Th1 subset. LPS and IL-1 had differential effects on the interference of the induction of tolerance in LPS-resistant mice where IL-1, but not LPS, was effective. In contrast to IL-1, IL-12 injected along with DHGG failed to interfere with the induction of tolerance in either Th1 or Th2 cells. Previous studies that demonstrated tolerance in the DHGG models induced in both the Th1 and Th2 subsets was further suggested by the demonstrations in the present study that dose-response curves for the induction of tolerance are identical in both subsets. The above findings taken together are compatible with the suggestion that tolerance induction results from the lack of cytokine production, which then prevents the expansion of Th1 and Th2 subsets following activation of the CD4+ precursor T cell. Furthermore, they support the general opinion that the expansion of these two subsets involve different cytokine pathways and that LPS and IL-1 most likely act through different cell receptors.

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CD4+ T-cell subsets and cytokines involved in peripheral tolerance

Cited by 32 publications

References 30 publications

Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells

Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells

Assessment of Immunologic Status of Liver Transplant Recipients by Peripheral Blood Mononuclear Cells in Response to Stimulation by Donor Alloantigen

Cytokines in the Induction and Circumvention of Peripheral Tolerance

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