Predominant Expression of T Helper 2 Cytokines and Altered Expression of T Helper 1 Cytokines in Long-Term Allograft Survival Induced by Intrathymic Immune Modulation With Donor Class I Major Histocompatibility Complex Peptides1,2

Shirwan, Haval; Barwari, Luqman; Khan, Nasreen

doi:10.1097/00007890-199812270-00039

Cited by 32 publications

(26 citation statements)

References 49 publications

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“…Tolerant hosts mounted potent antidonor proliferative responses and demonstrated anti-donor cytotoxic T cell frequencies that were equivalent to naive animals. Additionally, our results of intragraft cytokine elaboration patterns contrast those observed in tolerant recipients following anti-CD4 mAb therapy which is IL-4 predominant [34], or following intrathymic inoculation of class I allopeptides which induces dichotomized reduction of Th1 (IL-2 and IFN-γ) and predominant Th2 (IL-4 and IL-10) patterns [40]. Allochimeric conditioned recipients demonstrated predominant elaboration of IL-10, but not IL-4, and downregulation of Th1 (IL-2 and IFN-γ) cytokines.…”

Section: Discussioncontrasting

confidence: 73%

“…This strategy has previously suggested that the polymorphic sequences on the α 1 -helical regions RT1.A u and RT1.A l included immunogenic epitopes that induced accelerated rejection of RT1 u and RT1 I cardiac allografts in RT1 b recipients [25]. In concert with previous studies that utilized synthetic peptides derived from the polymorphyic RT1.A a regions [12,14] [24,39,40]. Further, pre-transplant peripheral administration of syngeneic dendritic cells (DCs) pulsed with immunogenic donor peptide (100 μg/ml) has induced robust peripheral tolerance [43][44][45].…”

Section: Discussionmentioning

confidence: 97%

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Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

Semiletova

Shen

Feldman

et al. 2007

Cellular Immunology

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Functional topography of rat class I major histocompatibility complex (MHC) molecule was studied. The α 1 -helical sequences that are shared by class I RT1.Al and RT1.A u were substituted in the RT1.A a molecule to produce the composite [α 1h l/u ]-RT1.A a MHC class I allochimeric molecule. Dominant immunogenic epitopes that induce accelerated rejection were identified within the hypervariable regions of the α 1 domain of RT1.A a , RT1.A l , and RT1.A u . Peritransplant portal venous delivery of MHC class I allochimeric proteins, that included composite α 1 helical immunodominant epitopes of RT1.A u and RT1.A l , induced donor-specific tolerance to RT1 u (Wistar Furth, WF) and RT1 l Lewis, LEW) disparate cardiac allografts in ACI (RT1 a ) hosts. Allochimeric generated tolerance was characterized by absence of T cell deletion or anergy. Donor specific IgM allo-Abs was not detected, while IgG alloresponse was markedly attenuated in sera of tolerant hosts. Further, long-term allografts in allochimeric-conditioned hosts exhibited moderate B cell infiltration when compared to rejecting controls. Analysis of intragraft cytokines revealed selective upregulation of IL-10 and marked inhibition of IL-2, IFN-γ and IL-4. Our findings indicate the emergence of a peripherally induced tolerant state, afforded by the novel approach of soluble class I allochimeric conditioning that presents donor immunogenic epitopes in the context of recipient class I determinants.

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Section: Discussioncontrasting

confidence: 73%

Section: Discussionmentioning

confidence: 97%

Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

Semiletova

Shen

Feldman

et al. 2007

Cellular Immunology

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“…5A). The major role of the active form of IL-12 (p70 IL-12) is to promote the differentiation of naive CD4 + T cells into Th1 cells, a cell type which is critically involved in acute allograft rejection [29]. A recent report from Viera et al [30] describes a new immunosuppressive compound, glatiramer acetate, which acted by favoring Th2 development through both inhibition of p70-IL12 secretion and enhanced IL-10 production.…”

Section: Discussionmentioning

confidence: 99%

A new carboxamide compound exerts immuno‐suppressive activity by inhibiting dendritic cell maturation

et al. 2005

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The immunosuppressive properties of a benzamide derivative, JM34, previously characterized as an anti-inflammatory compound are described. The immunosuppressive potential of JM34 was evidenced by inhibition of PBMC proliferation in vitro with an IC 50 of 20 lM. In contrast with classical immunosuppressive drugs, JM34 affected neither cytokine production nor IL-2R expression from activated T cell clones, and displayed only moderate inhibition of IL-2-induced or anti-CD3/anti-CD28-induced proliferation. We investigated its effects on dendritic cells (DC) in vitro. Addition of JM34 during DC maturation inhibited the expression of some maturation markers: specifically, MHC molecule up-regulation was totally inhibited and CD83 expression was significantly reduced, while up-regulation of CD86, CD80 or CD40 was less affected. Moreover, JM34-treated DC showed impaired IL-12 but not IL-10 secretion, and a markedly reduced ability to present antigens to naive T lymphocytes in vitro. We provide evidence that these JM34-induced alterations of DC were associated with a marked inhibition of NF-jB nuclear translocation. Finally, JM34 inhibited delayed type hypersensitivity dose dependently in mice. In conclusion, our data suggest that JM34 inhibited T lymphocyte activation mainly by targeting DC, and thus may represent a new class of therapeutic agents in the fields of transplantation and autoimmune diseases.

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“…It is widely proposed that Th1 cells promote allograft rejection and hinder tolerance induction, whereas Th2 responses favor a state of tolerance. These hypotheses come largely from the fact that, in multiple models, acute allograft rejection has been associated with the local presence of type 1 cytokine proteins or mRNA transcripts, whereas lack of rejection has correlated with the presence of type 2 cytokines (2)(3)(4). In addition, treatment with anti-IL-12 to prevent type 1 differentiation has resulted in prolonged allograft survival when acute rejection was dependent on indirect presentation of allopeptides or in the case of minor Ag-mismatched allografts (5).…”

mentioning

confidence: 99%

Role of STAT4 and STAT6 Signaling in Allograft Rejection and CTLA4-Ig-Mediated Tolerance

Zhou¹,

Szot²,

Guo³

et al. 2000

The Journal of Immunology

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STAT4−/− mice have impaired type 1 T cell differentiation, whereas STAT6−/− mice fail to generate type 2 responses. The role of type 1 and type 2 T cell differentiation in acute cardiac allograft rejection and in the induction of tolerance was examined in wild-type, STAT4−/−, and STAT6−/− recipients. All recipients rejected the grafts promptly. Analysis of in situ cytokine gene expression in the allografts confirmed decreased levels of IFN-γ in STAT4−/− recipients and undetectable levels of IL-4 and IL-5 in STAT6−/− mice. Blockade of the CD28/B7 costimulatory pathway prolonged cardiac graft survival for >100 days in 100% of wild-type and STAT4−/− mice. However, 14% of CTLA4-Ig-treated STAT6−/− mice rejected their grafts between 20 and 100 days. Moreover, of those animals followed past 100 days, 60% of the STAT6−/− mice rejected their grafts. Splenocytes harvested on day 145 posttransplant from CTLA4-Ig-treated rejecting STAT6−/− recipients were transfused into syngeneic SCID mice transplanted with donor or third party cardiac allografts. Both donor and third party grafts were rejected, indicating that the initial graft loss may be due to an immunological rejection. In contrast, when splenocytes from CTLA4-Ig-treated wild-type or nonrejecting STAT6−/− mice were transferred into SCID recipients, donor allografts were accepted, but third party hearts were rejected. Thus, long-term prolongation of cardiac allograft survival by CTLA4-Ig is STAT4-independent but, at least in part, STAT6-dependent. These data suggest that the balance of type 1 and type 2 T lymphocyte differentiation is not critical for acute rejection but influences the robust tolerance induced by CD28/B7 blockade in this model.

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Predominant Expression of T Helper 2 Cytokines and Altered Expression of T Helper 1 Cytokines in Long-Term Allograft Survival Induced by Intrathymic Immune Modulation With Donor Class I Major Histocompatibility Complex Peptides1,2

Cited by 32 publications

References 49 publications

Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

Class I MHC allochimeric presentation of composite immunogenic and self epitopes induces tolerance to genetically diverse rat strains

A new carboxamide compound exerts immuno‐suppressive activity by inhibiting dendritic cell maturation

Role of STAT4 and STAT6 Signaling in Allograft Rejection and CTLA4-Ig-Mediated Tolerance

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