Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy

Kühne, Louisa; Poth, Helen; Schuster, Antonia; Wurm, Simone; Ruemmele, Petra; Banas, Bernhard; Bergler, Tobias

doi:10.1186/s12865-017-0236-6

Cited by 12 publications

(15 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Primary tumour cells are one of the main constituents of tumour tissues and are reported to contribute to immune system suppression. For instance, tumour cells recruit Treg cells to tissues to suppress the activity of infiltrating immune cells or secrete multiple cytokines to sustain the immunosuppressive microenvironment to help tumour cells survive [18]. To uncover the underlying mechanism of the impairment of tumour-infiltrating NK cells in ESCC, we first sought to isolate primary ESCC cells in vitro.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

Gao

Wang

et al. 2019

J Exp Clin Cancer Res

127

110

View full text Add to dashboard Cite

Background Recurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Tumour-infiltrating natural killer cells (NK cells) display powerful cytotoxicity to tumour cells and play a pivotal role in tumour therapy. However, the phenotype and functional regulation of NK cells in oesophageal squamous cell carcinoma (ESCC) remains largely unknown. Methods Single cell suspensions from blood and tissue samples were isolated by physical dissociation and filtering through a 70 μm cell strainer. Flow cytometry was applied to profile the activity and function of NK cells, and an antibody chip experiment was used to identify and quantitate cytokine levels. We studied IL-6 and IL-8 function in primary oesophageal squamous carcinoma and NK cell co-cultures in vitro and by a xenograft tumour model in vivo. Western blotting was used to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Finally, we performed an IHC array to analyse IL-6/IL-8 (interleukin 6/interleukin 8) expression in 103 pairs of tumours and matched adjacent tissues of patients with ESCC to elucidate the correlation between IL-6 or IL-8 and clinical characteristics. Results The percentages of NK cells in both peripheral blood and tumour tissues from patients with ESCC were significantly increased in comparison with those in the controls and correlated with the clinical characteristics. Furthermore, the decrease in activating receptors and increase in inhibitory receptors on the surface of tumour-infiltrating NK cells was confirmed by flow cytometry. The level of granzyme B, the effector molecule of tumour-infiltrating NK cells, was also decreased. Mechanistically, primary ESCC cells activated the STAT3 signalling pathway on NK cells through IL-6 and IL-8 secretion, leading to the downregulation of activating receptors (NKp30 and NKG2D) on the surface of NK cells. An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function. Moreover, the expression of IL-6 or IL-8 in tumour tissues was validated by immunohistochemistry to be positively correlated with tumour progression and poor survival, respectively. Conclusions Tumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1310-0) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

“…It has been established that many components in tumour tissues modulate the activity of infiltrating lymphocytes to form an immunosuppressive environment [17, 18]. As the main constituent of tumour tissues, primary tumour cells have been reported to play a key role in the inhibition of infiltrating lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

Gao

Wang

et al. 2019

J Exp Clin Cancer Res

127

110

View full text Add to dashboard Cite

show abstract

“…donor-specific antibodies. Since donor-specific antibodies bind epitopes presented by mismatched organ's MHC, we used donor splenocytes as a surrogate for organ allografts for in vitro analysis (13,14). We therefore measured donor-specific antibodies in the sera of WT and D227K recipient mice after incubation with BALB/c donor cells and detection of surface-bound Ab with secondary anti-mouse IgG1.…”

Section: Resultsmentioning

confidence: 99%

Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Choi

Eskandari

Cai

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)–CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1–restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.

show abstract

“…By adjusting for HLA mismatch in our analysis, we attempted to minimize significant differences between recipients with no PACT assessment and a PACT assessment. Despite the known association of de novo donor specific antibodies (DSA) and non-adherence, baseline DSA and de novo DSA were not routinely screened in all patients at our institution until recently (17, 26, 27). Thus, it could not be included as a clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Psychosocial Assessment of Candidates for Transplantation (PACT) Score Identifies High Risk Patients in Pediatric Renal Transplantation

et al. 2019

View full text Add to dashboard Cite

Background: Currently, there is no standardized approach for determining psychosocial readiness in pediatric transplantation. We examined the utility of the Psychosocial Assessment of Candidates for Transplantation (PACT) to identify pediatric kidney transplant recipients at risk for adverse clinical outcomes. Methods: Kidney transplant patients <21-years-old transplanted at Duke University Medical Center between 2005 and 2015 underwent psychosocial assessment by a social worker with either PACT or unstructured interview, which were used to determine transplant candidacy. PACT assessed candidates on a scale of 0 (poor candidate) to 4 (excellent candidate) in areas of social support, psychological health, lifestyle factors, and understanding. Demographics and clinical outcomes were analyzed by presence or absence of PACT and further characterized by high (≥3) and low (≤2) scores. Results: Of 54 pediatric patients, 25 (46.3%) patients underwent pre-transplant evaluation utilizing PACT, while 29 (53.7%) were not evaluated with PACT. Patients assessed with PACT had a significantly lower percentage of acute rejection (16.0 vs. 55.2%, p = 0.007). After adjusting for HLA mismatch, a pre-transplant PACT score was persistently associated with lower odds of acute rejection (Odds Ratio 0.119, 95% Confidence Interval 0.027–0.52, p = 0.005). In PACT subsection analysis, the lack of family availability (OR 0.08, 95% CI 0.01–0.97, p = 0.047) and risk for psychopathology (OR 0.34, 95% CI 0.13–0.87, p = 0.025) were associated with a low PACT score and post-transplant non-adherence. Conclusions: Our study highlights the importance of standardized psychosocial assessments and the potential use of PACT in risk stratifying pre-transplant candidates.

show abstract

Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy

Cited by 12 publications

References 44 publications

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

Psychosocial Assessment of Candidates for Transplantation (PACT) Score Identifies High Risk Patients in Pediatric Renal Transplantation

Contact Info

Product

Resources

About