Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32)

Woo, Jacky; Iyer, Suhasini; Cornejo, Marie-Christine; Mori, N.; Gao, Lan; Sipos, I.; Maines, Mahin D.; Buelow, Roland

doi:10.1016/s0966-3274(98)80022-1

Cited by 106 publications

(86 citation statements)

References 43 publications

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“…Up-regulation of these genes blocks activation of the transcription factor NF-B in endothelial cell cultures, and thereby suppresses induction of proinflammatory genes in Ag-activated endothelium (21,34). We have recently shown striking cytoprotective effects of HO-1 overexpression in rat liver models of ischemia/reperfusion injury (35), consistent with other reports documenting the role of HO-1 overexpression in xenograft "accommodation" (36), prolonged allografts survival (37), or prevention of transplant arteriosclerosis and interstitial fibrosis characteristic for chronic rejection (38). Moreover, in a parallel Fas ligand gene therapy study in rat renal allografts (39), we have recently detected down-regulation of Bag-1, a prototype of a novel type of Bcl-2-binding anti-cell death gene, which has been implicated in T cell activation-induced apoptosis (40).…”

Section: Discussionsupporting

confidence: 89%

Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients

Ritter

Kato

et al. 2000

The Journal of Immunology

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We have previously shown that the tolerant state in allograft recipients can be maintained and perpetuated by an “infectious” T cell-dependent regulatory mechanism. Hence, 1) treatment of LEW rats with RIB-5/2, a CD4 nondepleting mAb, produces indefinite survival of LBNF1 cardiac allografts; 2) donor-specific tolerance can be then transferred by spleen cells into new cohorts of test allograft recipients; and 3) putative regulatory CD4+ Th2-like cells are instrumental in this tolerance model. We now report on studies aimed at exposing mechanisms underlying the infectious tolerance pathway, with emphasis on the interactions between intragraft adenovirus-IL-4 gene transfer and systemic infusion of regulatory cells from tolerant hosts. Unlike individual treatment regimens, adjunctive therapy with adenovirus-IL-4 and suboptimal doses of regulatory spleen cells was strongly synergistic and extended donor-type test cardiac allograft survival to about 2 mo. RT-PCR-based expression of intragraft mRNA coding for IL-2 and IFN-γ remained depressed, whereas that of IL-4 and IL-10 reciprocally increased selectively in the combined treatment group, data supported by ELISA studies. In parallel, only adjunctive treatment triggered intragraft induction of molecules with anti-oxidant (HO-1) and anti-apoptotic (Bcl-xL/Bag-1) but not with pro-apoptotic (CPP-32) functions, both in the early and late posttransplant phases. Hence, systemic infusion of regulatory cells potentiates the effects of local adenovirus-IL-4 gene transfer in transplant recipients. Th2-driven up-regulation of protective molecule programs at the graft site, such as of anti-oxidant HO-1 and/or anti-apoptotic Bcl-xL and Bag-1, may contribute, at least in part, to the maintenance of the infectious tolerance pathway in transplant recipients.

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Section: Discussionsupporting

confidence: 89%

Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients

Ritter

Kato

et al. 2000

The Journal of Immunology

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“…However, growing evidence has shown that HO-1 and its byproduct, CO, suppress T-cell proliferation [34,35]. The over-expression of HO-1 results in the inhibition of several immune effector functions and thus provides an explanation for stressinduced immunosuppression [36]. Moreover, human CD4 + CD25 + T-cell constitutively express HO-1 [26].…”

Section: Discussionmentioning

confidence: 99%

CD4+CD25+FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas

2007

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Regulatory T-cells play an important role in the regulation of the immune response and the mediation of dominant immunologic tolerance. We have previously shown that these cells are elevated in tumors and blood of patients with glioblastoma multiforme. Heme oxygenase-1, a rate-limiting enzyme in heme catabolism, has also been shown to accumulate during glioma progression and to play a critical role in FoxP3 mediated immune suppression. In this study, we investigated the correlation between FoxP3 and HO-1 expression in patients with various grades of astrocytoma (WHO grade II-IV). Using qualitative and quantitative reverse transcriptase-polymerase chain reaction and quantitative flow cytometry analyses, we analyzed FoxP3 and HO-1 expression in 19 patients with different grades of astrocytoma. We observed the highest level of FoxP3 expression in patients with grade IV tumors (11.54 ± 1.95%) vs. grade III (6.74 ± 0.19%) or grade II (2.53 ± 0.11%) (P < 0.05). Moreover, in grade IV tumors, the frequency of HO-1 mRNA expression in CD4 + CD25 + cells was 11.8 ± 2.45% vs. 7.42 ± 0.31% in grade III and 2.33 ± 0.12% in grade II. Tumor infiltrating Treg stained positively with anti-HO-1 antibody. The expression of HO-1 correlated with CD4 + CD25 + FoxP3 + infiltration (r = 0.966). Our results confirm that HO-1 expressing Treg accumulate during glioma progression. This study also suggests that HO-1 mRNA expression is linked to the induction of Foxp3 in CD4 + CD25 + glioma infiltrating Treg. These findings support the suppressive role played by regulatory T-cells in the growth of malignant brain tumors.

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“…Similar to our findings, increased HO-1 expression following the administration of immunoregulatory peptides or metalloporphyrins has been shown to prolong allograft survival moderately. [3][4][5][6][7] While these results suggest a potential role for HO-1 in prolonging allograft survival, immunomodulatory peptides and metalloprotoporphyrins exert other functions. [7][8][9] .…”

Section: Discussionmentioning

confidence: 99%

“…1,2 This suggests that HO-1 is involved not only in heme degradation and iron reutilization but also in tissue protection against a variety of cell injuries. 1,2 Recently, the overexpression of HO-1 has been associated with prolongation of graft survival following the administration of metalloporphyrins [3][4][5] or immunomodulatory peptides, 6,7 which modulate HO-1 activity. Unfortunately, metalloporphyrins can also modulate the action of other heme-containing molecules such as NO synthases (NOS) or soluble guanylate cyclases 8,9 and immunomodulatory peptides may have effects on other molecules independent of HO-1.…”

Section: Introductionmentioning

confidence: 99%

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

et al. 2004

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Elevated expression of heme oxygenase-1 (HO-1), an intracellular enzyme that degrades heme into carbon monoxide (CO), biliverdine and free iron, has anti-inflammatory and antiapoptotic effects in diverse models. Here, we analyzed the effects of specific overexpression of HO-1 following adenovirus-mediated (AdHO-1) gene transfer in an acute cardiac allograft rejection model. The intragraft (i.g.) injection of AdHO-1 into cardiac allografts, as well as intramuscular (i.m.) or intravenous (i.v.) administration, prolonged allograft survival with, respectively, 13.3, 62.5 and 80% of the grafts surviving long term (4100 days), whereas control grafts were rejected with acute kinetics. HO-1 overexpression was associated with inhibited allogeneic responses in MLRs using graft-infiltrating leukocytes and splenocytes, but not with lymph node cells. The inhibition of splenocyte proliferation was mediated by soluble factors and was dependent on the presence of APCs, since purified T cells proliferated normally. i.v. but not i.g. AdHO-1 administration decreased the number of graft-infiltrating leukocytes, cytokine mRNA accumulation and apoptosis in transplanted hearts, whereas i.v. and i.g. AdHO-1 did not modify normal immune responses against cognate antigens, indicating that there was no general immunosuppression. These results indicate that HO-1 overexpression prolongs the survival of vascularized allografts by promoting tolerogenic mechanisms acting on allogeneic cellular immune responses.

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Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32)

Cited by 106 publications

References 43 publications

Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients

Regulatory Cells Potentiate the Efficacy of IL-4 Gene Transfer by Up-Regulating Th2-Dependent Expression of Protective Molecules in the Infectious Tolerance Pathway in Transplant Recipients

CD4+CD25+FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas

Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer

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