Immunological Monitoring of Renal Transplant Recipients to Predict Acute Allograft Rejection Following the Discontinuation of Tacrolimus

Contains fulltext : 69863.pdf (publisher's version ) (Open Access)BACKGROUND: Transplant patients would benefit from reduction of immunosuppression providing that graft rejection is prevented. We have evaluated a number of immunological markers in blood of patients in whom tacrolimus was withdrawn after renal transplantation. The alloreactive precursor frequency of CD4+ and CD8+ T cells, the frequency of T cell subsets and the functional capacity of CD4+CD25+FoxP3+ regulatory T cells (Treg) were analyzed before transplantation and before tacrolimus reduction. In a case-control design, the results were compared between patients with (n = 15) and without (n = 28) acute rejection after tacrolimus withdrawal. PRINCIPAL FINDINGS: Prior to tacrolimus reduction, the ratio between memory CD8+ T cells and Treg was higher in rejectors compared to non-rejectors. Rejectors also had a higher ratio between memory CD4+ T cells and Treg, and ratios <20 were only observed in non-rejectors. Between the time of transplantation and the start of tacrolimus withdrawal, an increase in naive T cell frequencies and a reciprocal decrease of effector T cell percentages was observed in rejectors. The proportion of Treg within the CD4+ T cells decreased after transplantation, but anti-donor regulatory capacity of Treg remained unaltered in rejectors and non-rejectors. CONCLUSIONS: Immunological monitoring revealed an association between acute rejection following the withdrawal of tacrolimus and 1) the ratio of memory T cells and Treg prior to the start of tacrolimus reduction, and 2) changes in the distribution of naive, effector and memory T cells over time. Combination of these two biomarkers allowed highly specific identification of patients in whom immunosuppression could be safely reduced

Defining Early Human NK Cell Developmental Stages in Primary and Secondary Lymphoid Tissues

A better understanding of human NK cell development in vivo is crucial to exploit NK cells for immunotherapy. Here, we identified seven distinctive NK cell developmental stages in bone marrow of single donors using 10-color flow cytometry and found that NK cell development is accompanied by early expression of stimulatory co-receptor CD244 in vivo. Further analysis of cord blood (CB), peripheral blood (PB), inguinal lymph node (inLN), liver lymph node (liLN) and spleen (SPL) samples showed diverse distributions of the NK cell developmental stages. In addition, distinctive expression profiles of early development marker CD33 and C-type lectin receptor NKG2A between the tissues, suggest that differential NK cell differentiation may take place at different anatomical locations. Differential expression of NKG2A and stimulatory receptors (e.g. NCR, NKG2D) within the different subsets of committed NK cells demonstrated the heterogeneity of the CD56brightCD16+/− and CD56dimCD16+ subsets within the different compartments and suggests that microenvironment may play a role in differential in situ development of the NK cell receptor repertoire of committed NK cells. Overall, differential in situ NK cell development and trafficking towards multiple tissues may give rise to a broad spectrum of mature NK cell subsets found within the human body

Internal mammary lymph node recurrence: rare but characteristic metastasis site in breast cancer

<p>Abstract</p> <p>Background</p> <p>To assess the frequency of IMLN recurrence, its associated risk factors with disease-free interval (DFI) and its predicting factors on overall survival time.</p> <p>Methods</p> <p>133 cases of breast cancer IMLN recurrence were identified via the computerized CT reporting system between February 2003 and June 2008, during which chest CT for patients with breast cancer (n = 8867) were performed consecutively at Cancer Hospital, Fudan University, Shanghai, China. Patients' charts were retrieved and patients' characteristics, disease characteristics, and treatments after recurrence were collected for analysis. The frequency was 1.5% (133/8867).</p> <p>Results</p> <p>IMLN recurrence was presented as the first metastatic site in 121 (91%) patients while 88 (66.2%) had other concurrent metastases. Typical chest CT images included swelling of the IMLN at the ipsilateral side with local lump and sternal erosion located mostly between the second and third intercostal space. The median disease-free interval (DFI) of IMLN recurrence was 38 months. The independent factors that could delay the IMLN recurrence were small tumor size (HR 0.5 95%CI: 0.4 - 0.8; <it>p </it>= 0.002), and positive ER/PR disease (HR 0.6, 95% CI: 0.4 - 0.9; <it>p </it>= 0.006). The median survival time after IMLN recurrence was 42 months, with a 5-year survival rate of 30%. Univariate analysis showed four variables significantly influenced the survival time: DFI of IMLN recurrence (p = 0.001), no concurrent distant metastasis (p = 0.024), endocrine therapy for patients with positive ER/PR (p = 0.000), radiotherapy (p = 0.040). The independent factors that reduced the death risk were no concurrent distant metastases (HR: 0.7, 95% CI: 0.4 - 0.9; <it>p </it>= 0.031), endocrine therapy for patients with positive ER/PR status (HR: 0.2, 95% CI: 0.1 - 0.5; <it>p </it>= 0.001) and palliative radiotherapy (HR: 0.3, 95% CI: 0.1- 0.9; <it>p </it>= 0.026).</p> <p>Conclusions</p> <p>The risk of IMLN recurrence is low and there are certain characteristics features on CT images. ER/PR status is both a risk factor for DFI of IMLN recurrence and a prognostic factor for overall survival after IMLN recurrence. Patients with only IMLN recurrence and/or local lesion have a good prognosis.</p

Diagnosis, treatment and prognosis of internal mammary lymph node recurrence in breast cancer patients

Recurrences in the internal mammary lymph nodes (IMLN) are very rare, despite the fact that these nodes remain untreated in most patients. The aim of this study was to assess the chance for IMLN recurrence in a large patient series and to get insight into diagnostics, treatment and prognosis of this type of recurrence. Follow-up of nearly 6000 breast cancer patients resulted in the tracing of only six patients with IMLN recurrence. IMLN recurrence was defined as breast cancer recurrence in an internal mammary lymph node without a distant metastasis before the recurrence and confirmed by cytology and/or CT-scan. The time interval between diagnosis of the primary tumor and the recurrence varied between 5 months and 8 years and 6 months. One patient showed no symptoms, the other five all had a swelling and one of them also had pain. The size of the parasternal swelling varied from 30 to 90 mm; in one patient the size was unknown. Treatment resulted in a complete remission in four patients. In five of the six patients distant metastases occurred. The time interval between IMLN recurrence and the diagnosis of distant metastasis varied between 0 and 37 months. One patient was still free of distant metastasis in the time of this study. This large population-based study confirms the almost negligible risk of clinically apparent IMLN recurrence. Considering the high percentage of positive lymph nodes in studies evaluating sentinel node biopsy of the internal mammary chain, it becomes clear that just a fraction of these becomes clinically apparent as a recurrence. In almost all patients with IMLN it is a forerunner of metastatic disease

Long-term prognosis of patients with axillary recurrence after axillary dissection for invasive breast cancer.

Item does not contain fulltextAIM: To investigate the long-term prognosis of patients with axillary recurrence after axillary dissection for invasive breast cancer and describe the long-term survivors. METHODS: Between 1984 and 1994, 4669 patients with invasive breast cancer underwent axillary dissection in eight community hospitals in the south-eastern part of The Netherlands. Using follow-up data of the population-based Eindhoven Cancer Registry, 59 patients with axillary recurrence were identified. RESULTS: The median interval between treatment of the primary tumour and diagnosis of axillary recurrence was 2.6 years (range 0.3-10.7). The median length of follow-up after diagnosis of axillary recurrence was 11.1 years (5.7-15.6). Distant metastases occurred in 38 of the 59 patients. The 5- and 10-year distant recurrence-free survival rates were 39% (95% CI: 25-52%) and 29% (95% CI: 16-42%). CONCLUSIONS: Axillary recurrence following axillary dissection is associated with a high rate of subsequent distant metastasis and poor overall prognosis but is not always a fatal event. Our results show that it is possible to cure about one-third of the patients

Platelet-derived microparticles inhibit IL-17 production by regulatory T cells through P-selectin

Contains fulltext : 165738.pdf (publisher's version ) (Closed access)Self-tolerance and immune homeostasis are orchestrated by FOXP3(+)regulatory T cells (Tregs). Recent data have revealed that upon stimulation, Tregs may exhibit plasticity toward a proinflammatory phenotype, producing interleukin 17 (IL-17) and/or interferon gamma (IFN-gamma). Such deregulation of Tregs may contribute to the perpetuation of inflammatory processes, including graft-versus-host disease. Thus, it is important to identify immunomodulatory factors influencing Treg stability. Platelet-derived microparticles (PMPs) are involved in hemostasis and vascular health and have recently been shown to be intimately involved in (pathogenic) immune responses. Therefore, we investigated whether PMPs have the ability to affect Treg plasticity. PMPs were cocultured with healthy donor peripheral blood-derived Tregs that were stimulated with anti-CD3/CD28 monoclonal antibodies in the presence of IL-2, IL-15, and IL-1beta. PMPs prevented the differentiation of peripheral blood-derived Tregs into IL-17- and IFN-gamma-producing cells, even in the presence of the IL-17-driving proinflammatory cytokine IL-1beta. The mechanism of action by which PMPs prevent Treg plasticity consisted of rapid and selective P-selectin-dependent binding of PMPs to a CCR6(+)HLA-DR(+)memory-like Treg subset and their ability to inhibit Treg proliferation, in part through CXCR3 engagement. The findings that approximately 8% of Tregs in the circulation of healthy individuals are CD41(+)P-selectin(+)and that distinct binding of patient plasma PMPs to Tregs was observed support in vivo relevance. These findings open the exciting possibility that PMPs actively regulate the immune response at sites of (vascular) inflammation, where they are known to accumulate and interact with leukocytes, consolidating the (vascular) healing process

Prominent HLA-G Expression in Liver Disease But Not After Liver Transplantation

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