Contribution of CD4+ and CD8+ T-cells in contact hypersensitivity and allergic contact dermatitis

Allergic contact dermatitis, also referred to as contact hypersensitivity, is one the most frequent inflammatory skin diseases, and is characterized by redness, papule and vesicles, followed by scaling and dryness. Allergic contact dermatitis is elicited upon skin contact with nonprotein chemicals, haptens, and corresponds to a cutaneous delayed type hypersensitivity reaction, mediated by hapten-specific T-cells. During the sensitization phase, both CD4⁺ and CD8⁺ T-cell precursors are activated in the draining lymph nodes by presentation of haptenated peptides by skin dendritic cells. Subsequent hapten painting on a remote skin site induces the recruitment and activation of specific T-cells at the site of challenge. This leads to apoptosis of keratinocytes, recruitment of inflammatory cells and development of clinical symptoms. Experimental studies from the last 10 years have demonstrated that, in normal contact hypersensitivity responses to strong haptens, CD8⁺ type 1 T-cells are effector cells of contact hypersensitivity through cytotoxicity and interferon-γ production, while CD4⁺ T-cells are endowed with downregulatory functions. The latter may correspond to the recently described CD4⁺CD25⁺ regulatory T-cell population. However, in some instances, especially when there is a deficient CD8⁺ T-cell pool, CD4⁺ T-cells can be effector cells of contact hypersensitivity. Ongoing studies will have to confirm that the pathophysiology of human allergic contact dermatitis is similar to the mouse contact hypersensitivity and that the contact hypersensitivity response to common weak haptens, most frequently involved in human allergic contact dermatitis, is similar to that reported for strong haptens.     

Novel Immunotherapeutic Strategies in Development for Renal Cell Carcinoma

Context

The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase.

Objective

To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm.

Evidence acquisition

A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy.

Evidence synthesis

Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host–tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies.

Conclusions

It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy.     

Immunomagnetic T-Lymphocyte Depletion (ITLD) of Rat Bone Marrow Using OX-19 Monoclonal Antibody

Graft versus host disease (GVHD) may be abrogated and host survival prolonged by in vitro depletion of T lymphocytes from bone marrow (BM) prior to allotransplantation. Using a mouse anti-rat pan T-lymphocyte monoclonal antibody (0×19) bound to monosized, magnetic, polymer beads, T lymphocytes were removed in vitro from normal bone marrow. The removal of the T lymphocytes was confirmed by flow cytometry. Injection of the T-lymphocyte-depleted bone marrow into fully allogeneic rats prevents the induction of GVHD and prolongs host survival.

A highly efficient technique of T-lymphocyte depletion using rat bone marrow is described. It involves the binding of OX-19, a MoAb directed against all rat thy-mocytes and mature peripheral T lymphocytes, to monosized, magnetic polymer spheres. Magnetic separation of T lymphocytes after mixing the allogeneic bone marrow with the bead/OX-19 complex provides for a simple, rapid depletion of T lymphocytes from the bone marrow. In vitro studies using flow cytometry and the prevention of GVHD in a fully allogeneic rat bone marrow model have been used to demonstrate the effectiveness of the depletion procedure.     

Longitudinal study of levodopa in Parkinson's disease: Effects of the advanced disease phase

Thirty‐four patients have been studied from the time of initiation of pharmacological treatment in a long‐term prospective study of levodopa effects and disease progression in Parkinson's disease. Objective motor scoring of the response to levodopa in defined off states was performed every 3 years. The mean time from the initiation of levodopa treatment to the most recent measurements was 18.2 years. Of 8 patients who are still alive, only 3 had none of the features of the advanced disease phase (dementia, hallucinations, frequent falling). Off‐phase motor function worsened at a yearly rate of 1.9% of the maximum disability score, although the plots of the serial scores showed that the magnitude of the levodopa response is well preserved. There was little difference in the rate of progression between patients with tremor‐dominant and non‐tremor‐dominant motor subtypes. Those who developed dementia had more rapid deterioration of motor scores, with significantly worse off‐phase (P = .008) and on‐phase (P = .03) motor function. A graph of serial scores of patients who have died, aligned for time of death, showed an upward curving trend of motor disability in the last 5 years of the disease course. Its advanced phase may reveal that Parkinson's disease has an exponential pattern of progression. © 2013 Movement Disorder Society     

组织病理学分型在胰腺导管内乳头状黏液性肿瘤中的临床意义

胰腺导管内乳头状黏液性肿瘤(IPMN)是一类少见的胰腺囊性肿瘤,以胰腺导管上皮细胞乳头状异常增生合并大量黏液产生为特点。IPMN根据累及胰管不同,可以分为主胰管型、分支胰管型及混合型,病理学上表现为腺瘤至浸润癌多种类型。根据细胞形态及表达黏蛋白不同,可以分为胃型、肠型、胰胆管型及嗜酸细胞型。笔者结合既往文献及团队实践经验,分析组织病理学分型在胰腺IPMN中的临床意义,旨在提高外科医师对胰腺IPMN不同组织病理学类型的认识。     

Depression subtypes,binge eating,and weight loss in bariatric surgery candidates

BackgroundDepression and binge eating disorder (BED) are prevalent among bariatric surgery candidates. Depression subtypes may be differentially related to obesity, such that the atypical subtype predicts poorer outcomes. However, no research has examined depression subtypes, BED, and weight loss in bariatric candidates.ObjectiveTo examine whether presurgical atypical depressive symptoms, compared with no depressive and melancholic depressive symptoms, were associated with higher rates of presurgical BED, binge eating severity, and poorer postsurgical weight loss trajectories among bariatric candidates.SettingAn outpatient Midwest bariatric clinic.MethodsParticipants were 345 adults (aged 46.27 ± 12.78 yr, 76% female; body mass index = 49.84 ± 8.51 kg/m²) who received a presurgical evaluation. Depression subtypes (melancholic, atypical, and no depressive symptoms) were categorized using the Beck Depression Inventory-II. BED diagnosis and severity were evaluated using the Eating Disorder Diagnostic Scale and Binge Eating Scale, respectively. Weight loss trajectories were calculated as percent total weight loss postsurgery.ResultsUsing no depression as the referent, participants reporting melancholic symptoms (odds ratio = 7.60, P < .001 confidence interval₉₅ [2.59–22.28]) and atypical symptoms (odds ratio = 10.11, P < .01 confidence interval₉₅ [2.69–37.94]) were more likely to meet criteria for BED. Patients with atypical depressive symptoms exhibited the highest binge eating severity scores (mean = 23.03). Depression subtypes did not predict percent total weight loss trajectories within 18-months postbariatric surgery.ConclusionsPatients reporting preoperative atypical depressive symptoms were more likely to meet criteria for co-morbid BED diagnosis and have greater binge eating severity but did not have poorer weight loss within 18 months postsurgery. Future studies with longer-term follow-up and corresponding measures of postsurgical depression and binge eating pathology are warranted.     

Macrophage subtype and cytokine expression characterization during the acute inflammatory phase of mouse bone fracture repair

Fracture repair is a complex process requiring heterotypic interactions between osteogenic cells and immune cells. Recent evidence indicates that macrophages are critically involved in fracture repair. Polarized macrophage populations differentially promote and regulate inflammation in other tissues, but little is known about the various macrophage subtypes and their signaling activities following a bone fracture. The authors hypothesized that classically activated (M1 subtype) and alternatively activated (M2 subtype) macrophages are active during the early repair process to initiate and regulate the inflammatory response. To test our hypothesis, bone marrow was collected from intact femurs (naïve group), contralateral and fractured femurs of mice on days 0, 1, 2, 4, and 7 postfracture. Macrophages were isolated from the bone marrow and macrophage subtypes were identified using flow cytometry with antibodies to F4/80, MHC II, CD86, CD11c, and CD40. Bone marrow cytokine levels were measured using xMAP. Flow cytometry revealed dynamic changes in M1 subtype (F4/80+/MHC II+/CD86+), M2 subtype (F4/80+/MHC II−/CD86−), and dendritic cell (DCs; MHCII+/CD11c+/CD40+) populations following fracture as compared to naïve controls. M1 subtype levels were correlated with IL-1α, IL-1ß, IL-2, IL-17, Eotaxin, and MCP-1, while DCs were correlated with IL-6, G-CSF, LIF, KC, and VEGF-A. The results indicate that M1 and M2 subtypes and DCs are recruited to the fracture site early during the repair process and consequently may work in tandem to regulate the inflammatory response required to recruit osteogenic cells needed for later stages of repair.     

手足口病并发脑炎患儿免疫功能及与病情严重程度的关系研究

目的：探讨手足口病并发脑炎患儿免疫功能及与病情严重程度的关系。方法：收集2010年6月至2013年6月我院收治的180例手足口病患儿的临床资料,根据病情严重程度分为重症组（并发脑炎组）72例和轻症组（无脑炎组）108例,以120例同期同龄健康体检儿童为对照组。采用流式细胞仪进行T细胞亚群CD3＋、CD4＋、CD8＋水平的测定,同时采用免疫比浊法进行免疫球蛋白IgM、IgG、IgA水平的检测。结果：180例手足口病患儿CD3＋、CD4＋及CD8＋水平及免疫球蛋白IgM、IgG、IgA水平均低于健康对照组,差异均有统计学意义（P〈0．05）;重症组患儿CD3＋、CD4＋及CD8＋水平及免疫球蛋白IgM、IgG、IgA水平均低于轻症组,两组比较差异均有统计学意义（P〈0．05）。结论：手足口病患儿特别是合并有脑炎的重症手足口病患儿存在明显的免疫功能低下及免疫调节紊乱．因此在手足口病患儿的治疗过程中．应注意增强免疫支持治疗。