No abstract

Interferon-c (IFN-c)-preactivated mesenchymal stem cells (MSC-c) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrowderived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-c, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. SIGNIFICANCE STATEMENTMesenchymal stem cells (MSC) are potent and promising immunomodulatory cell therapy that have progressed into the clinic for allotransplantation. Cytokine modified MSC show superior immunosuppressive properties compared to unmodified MSC. In this study, we describe the enhanced immunosuppressive properties of MSC generated under the influence of the proinflammatory cytokine interleukin-17A (MSC-17) compared to interferon-gamma pre-treated MSC (MSC-c). Specifically these human MSC-17 have translational potential in transplantation protocols because they do not express MHC class II, thereby reducing their immunogenicity, in addition to avidly promote the formation of induced T regulatory cells.

Cutaneous squamous cell cancer (SCC) affects up to 30% of kidney transplant recipients (KTRs) within 10 years of transplantation. There are no reliable clinical tests that predict those who will develop multiple skin cancers. High numbers of regulatory T cells associate with poor prognosis for patients with cancer in the general population, suggesting their potential as a predictive marker of cutaneous SCC in KTRs. We matched KTRs with (n ϭ 65) and without (n ϭ 51) cutaneous SCC for gender, age, and duration of immunosuppression and assessed several risk factors for incident SCC during a median follow-up of 340 days. Greater than 35 peripheral FOXP3 ϩ CD4 ϩ CD127 low regulatory T cells/l, Ͻ100 natural killer cells/l, and previous SCC each significantly associated with increased risk for new cutaneous SCC development (hazard ratio [HR] 2.48 [95% confidence interval (CI) 1.04 to 5.98], HR 5.6 [95% CI 1.31 to 24], and HR 1.33 [95% CI 1.15 to 1.53], respectively). In addition, the ratio of CD8/FOXP3 expression was significantly lower in cutaneous SCC excised from KTRs (n ϭ 25) compared with matched SCC from non-KTRs (n ϭ 25) and associated with development of new cutaneous SCCs. In summary, monitoring components of the immune system can predict development of cutaneous SCC among KTRs.

Background: Cardiovascular morbidity and mortality remain high in recipients of a kidney transplant. The persistence of a patent arteriovenous fistula (AVF) after transplantation may contribute to ongoing maladaptive cardiovascular remodeling. The ability to reverse this maladaptive remodeling by ligation of this AVF is unknown. We conducted the first randomized controlled trial to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients. Methods: In this randomized controlled trial, kidney transplant recipients (>12 months after transplantation with stable graft function) were randomized to AVF ligation or no intervention. All participants underwent cardiac magnetic resonance imaging at baseline and at 6 months. The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, left and right atrial areas, LV ejection fraction, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, cardiac output/index, brachial flows (ipsilateral to AVF), and pulmonary artery velocity. Results: A total of 93 patients were screened, of whom 64 met the inclusion criteria and were randomized to the AVF ligation (n=33) or control (n=31) group. Fifty-four participants completed the study: 27 in the AVF ligation group and 27 in the control group. On the second cardiac magnetic resonance scan, a mean decrease of 22.1 g (95% CI, 15.0–29.1) was observed in LV mass in the AVF ligation group compared with a small increase of 1.2 g (95% CI, −4.8 to 7.2) in the control group ( P <0.001). Significant decreases in LV end-diastolic volumes, LV end-systolic volumes, cardiac output, cardiac index, atrial volumes, and NT-proBNP were also seen in the AVF closure group ( P <0.01). No significant changes were observed in LV ejection fraction ( P =0.93) and pulmonary artery velocity ( P =0.07). No significant complications were noted after AVF ligation. No changes in estimated glomerular filtration rate or systolic and diastolic blood pressures were observed between cardiac magnetic resonance scans. Conclusions: Elective ligation of patent AVF in adults with stable kidney transplant function resulted in clinically significant reduction of LV myocardial mass. Clinical Trial Registration: Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au . Unique Identifier: ACTRN12613001302741.

No abstract

High regulatory T-cell (Treg) numbers predict recurrent cutaneous squamous cell carcinoma in kidney transplant recipients, and the Treg immune phenotype may identify kidney transplant recipients at risk of developing squamous cell carcinoma and/or solid-organ cancer. To investigate this, a total of 116 kidney transplant recipients, of whom 65 had current or past cancer, were immune-phenotyped and followed up prospectively for a median of 15 months. Higher Treg (CD3+CD4+FOXP3+CD25(Hi)CD127(Lo)) proportion and numbers significantly increased the odds of developing cancer (odds ratios (95% CI) 1.61 (1.17-2.20) and 1.03 (1.00-1.06), respectively) after adjusting for age, gender, and duration of immunosuppression. Class-switched memory B cells (CD19+CD27+IgD-) had a significant association to cancer, 1.04 (1.00-1.07). Receiver operator characteristic (ROC) curves for squamous cell carcinoma development within 100 days of immune phenotyping were significant for Tregs, memory B cells, and γδ T cells (AUC of 0.78, 0.68, and 0.65, respectively). After cancer resection, Treg, NK cell, and γδ T-cell numbers fell significantly. Immune-phenotype profiles associated with both squamous cell carcinoma and solid-organ cancer in kidney transplant recipients and depended on the presence of cancer tissue. Thus, immune profiling could be used to stratify kidney transplant recipients at risk of developing cancers to identify those who could qualify for prevention therapy.

BK viral infection is an important cause of renal transplant dysfunction and failure. Current strategies utilize surveillance for infection with DNA polymerase chain reaction assays and modulation of immunosuppression. Many viruses including polyomaviruses encode microRNAs (miRNAs). We have detected BK virus (BKV) encoded miRNAs in the blood of infected renal transplant recipients, and see a strong correlation between BKV encoded miRNA and BKV DNA in blood and a relationship between levels of bkv‐miR‐B1‐5p and the presence of biopsy‐proven BK viral nephropathy. Further research is needed to determine whether the detection of this and other virally encoded miRNAs may be useful in the diagnosis of active viral replication.

These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers.