Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency.

The inhibitory anti-CTLA-4 antibody, ipilimumab, dramatically improved survival in a subgroup of metastatic melanoma patients. The majority, however, suffered autoimmune-related adverse events (irAEs), sometimes pathognomonic of acute graft-versus-host-disease (GVHD). This implies that the CTLA-4 blockade is not tumor specific.

A novel method of CD34+ cell separation from umbilical cord blood.

Background: Umbilical cord blood (UCB) is rich in the heavily glycosylated CD34 antigen-bearing hematopoietic stem cells that are valuable for transplantation therapy of malignant and nonmalignant disease. CD34+ cell yields (0.13%-0.

Current and historical perspectives on methodological flaws in processing umbilical cord blood.

Umbilical cord blood (UCB) hematopoietic stem cells (HSC-CD34+) are valuable for treating malignant or nonmalignant disease. Processing UCB by HESPAN-6% and anti-CD34-Miltenyi particles provides insufficient cells for treating adults. Physicochemical-electrokinetic studies on UCB-mononuclear cells (MNCs) under conditions of delayed processing, ice or very low temperatures, and some cell separation media identified artifacts introduced by procedures.

Interesting possibilities to improve the safety and efficacy of ipilimumab (Yervoy).

As predicted, an anti-CTLA-4 mAb (ipilimumab) on binding to T lymphocytes breaks down immune-tolerance. Thereby, it was hoped, tumor-specific-T cells would be freed for a sustained attack on cancer cells. Data on ipilimumab treatment in 1498 patients with advanced melanoma (in 14 phase I-III trials) has shown immune-related adverse events (irAEs) in 64.

Ipilimumab (Yervoy) and the TGN1412 catastrophe.

The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy) immune regulatory therapy was based on the premise that "Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication…" (Weber, 2009). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer.

Breast and other cancer dormancy as a therapeutic endpoint: speculative recombinant T cell receptor ligand (RTL) adjuvant therapy worth considering?

Background: Most individuals who died of trauma were found to harbour microscopic primary cancers at autopsies. Surgical excision of the primary tumour, unfortunately, seems to disturb tumour dormancy in over half of all metastatic relapses.

Presentation Of The Hypothesis: A recently developed immune model suggested that the evolutionary pressure driving the creation of a T cell receptor repertoire was primarily the homeostatic surveillance of the genome.

Reduction in high blood tumor necrosis factor-alpha levels after manipulative therapy in 2 cervicogenic headache patients.

Objective: This case report discusses the treatment of 2 patients with cervicogenic headache (CHA) attending the Outpatient Clinic of the Hungarian National Institute for Rheumatology and Physiotherapy (Budapest, Hungary) and reviews the pathophysiology, therapeutic strategy, and problems associated with the treatment of CHA.

Clinical Features: Patient 1 was a 27-year-old female who sustained a whiplash injury. A sharp, shooting headache developed, readily induced, and aggravated by just bending the neck backward or by turning her head.

T cells survey the stability of the self: a testable hypothesis on the homeostatic role of TCR-MHC interactions.

In the lifetime of an individual, every single gene will have undergone mutation on about 10(10) separate occasions. Nevertheless, cancer occurs mainly with advancing age. Here, we hypothesize that the evolutionary pressure driving the creation of the T cell receptor (TCR) repertoire was primarily the homeostatic surveillance of the genome.

Some aspects of the recombinantly expressed humanised superagonist anti-CD28 mAb, TGN1412 trial catastrophe lessons to safeguard mAbs and vaccine trials.

We consider essential, still ignored, basic research aspects of the failed clinical trial (13 March 2006) of a recombinantly expressed humanised superagonist anti-CD28 mAb, TGN14122. Without hindsight, if for approval of the first ever recombinantly expressed anti-CD28 mAb use in humans attention had been paid to the physico-chemical factors and receptor saturation, the possible catastrophe will have been predictable and preventable. To understand what went wrong and, crucially, to prevent any future disasters to safeguard human health, safety and welfare, the information provided is likely to be of wide interest.

Examination of the value of treatment of decompensated viral hepatitis patients by intentionally coinfecting them with an apathogenic IBDV and using the lessons learnt to seriously consider treating patients infected with HIV using the apathogenic hepatitis G virus.

Hepatitis virus infection persistent worldwide (approximately 600 m people) results in chronic hepatitis progressing to hepatocellular carcinoma (HCC) in many (approximately 1 m deaths/year). The review examines the usefulness of treating chronic viral hepatitis, including decompensated patients, by intentional coinfection with an attenuated infectious bursal disease virus (IBDV; apathogenic in man, stable at pH 2, orally administered). Learning lessons from the IBDV studies, the case is made to treat human immunodeficiency virus (HIV) infected patients (worldwide prevalence approximately 50 m people) by coinfecting with apathogenic hepatitis G virus (GBV-C).

Micromolar A and B blood group active trisaccharides abolish human complement haemolytic activity assayed by erythrocytes.

Background: At present, there is really no satisfactory treatment of severe haemolytic transfusion reactions involving the ABO system other than the use of steroids that at best are palliative in their effects. In contrast, the use of micromolar concentrations of A or B blood group active trisaccharides that are inexpensive and readily available may prevent lysis by generating soluble immune complexes (ICs) that consume complement. The purpose of this study was to determine the total lytic activity of human serum and to estimate the extent to which trisaccharides can exhaust this capacity.

Electrophoresis of cells and the biological relevance of surface charge.

Recent developments in electrophoresis of cells are reviewed. Problems and progress in automation and miniaturization of analytical electrophoresis instruments as well as in the interpretation of experimentally determined electrophoretic mobility (EPM) data are summarized: In recent times, the EPM determination techniques not only became more reliable and faster, but also more knowledge could be gained about the cell surface electrical properties, the structure of the glycocalyx as well as its influence on the cell peripheral regions and microenvironment by applying cell electrophoresis. In addition, ways are shown to solve discrepancies between physical requirements of a preparative cell electrophoresis procedure and the quantities of ions, which have to be dissolved in cell suspension media.

Some aspects of complementarity in the immune system. A bird's eye view.

The burden of this paper is the suggestion that the defence capacity of the immune system is rather limited. It cannot stand in readiness to deal with a practically endless diversity and abundance of microbes. In contrast to conventional thinking the current model proposes: (1) The core idea that cells of the immune system are basically and constantly interconnected with host cells (e.

Isolation procedures for blood lymphocytes produce artifacts. Detection by changes of electrophoretic mobilities of lymphocytes.

The changes induced in the distribution of the electrophoretic mobility (EPM) of human peripheral blood lymphocytes (HPBL), by various methods used to prepare the lymphocyte suspensions and eliminate platelets from them, were investigated on blood samples collected from healthy individuals and thrombopenic patients. Data showed that the distribution of the lymphocyte EPMs, i.e.

Opiate receptors on lymphocytes and platelets in man.

Receptors for opiates, opiate-like substances, and their antagonists, such as naloxone (a close chemical and conformational congener of morphine), on brain cell homogenates and neuroblastoma X glioma hybrid cells in tissue culture have been reported. The present study on the binding of [3H]naloxone to lymphocytes and platelets freshly isolated from the peripheral blood of 39 healthy adult human volunteers showed that (1) [3H]naloxone bound to lymphocytes and platelets at 4 degrees C, reaching equilibrium in 30 min, and was not removed by washing (three times) with the suspending medium; (2) the binding of [3H]naloxone to cells decreased in the presence of increasing amounts of unlabeled naloxone, approaching a plateau; (3) significant amounts of the radioligand remained bound in the presence of micromolar quantities of the unlabeled ligand; and (4) in the absence of Na+ ions, 1 to 10 nmol of morphine hydrochloride for 10(6) lymphocytes, and 1 to 25 nmol of morphine hydrochloride for 10(8) platelets, decreased the binding of [3H]naloxone by 43 to 57%. It is concluded that at least some of the [3H]naloxone binding sites on human lymphocytes and platelets are specific opioid receptor sites of the mu type (Enkephalins define the delta sites.

Lymphocyte thyroid hormone receptors in obesity.

Triiodothyronine (T3)-receptor characteristics of isolated circulating human mononuclear cells have been studied in a group of obese patients who claimed to be unable to lose weight on conventional 4.2 MJ (1000 kcal) diets. The cells of the obese patients exhibited a lower receptor capacity than those of a control group of non-obese subjects but the difference was not significant.

The role of T3 and its receptor in efficient metabolisers receiving very-low-calorie diets.

Obese patients taking a 1.34 MJ/day formula diet showed a steady decline in the rate of weight loss after several weeks and this was associated with a fall in RMR, serum T3 levels and the number of T3 receptors on peripheral lymphocytes. The addition of T3 (60 micrograms/day) to the dietary regime produced a significantly greater weight loss by the 12th week.

Age-dependent changes in the electrophoretic mobilities of human blood lymphocytes.

The distribution of the anodic electrophoretic mobilities (EPM) of human peripheral blood lymphocytes was determined for lymphocytes isolated from umbilical cord blood and from blood of individuals 6 months to 93 years of age. The distribution was bimodal in infants up to 2 years of age and suggested a small percentage of cells with a mobility of 0.95 micrometer s-1 V-1 cm.

[Genetic control of the H-2 region of the cell surface: cationic amino groups in the periphery of T lymphocytes].

Spleen lymphocytes and erythrocytes from congenic mice of diffrent haplotypes were characterized on a precise biophysical basis (the anodic electrophoretic mobility, EPM) to correlate any subtle differences in the cell surface topochemistry with the H-2 specificity. Spleen T lymphocytes from A.CA (H-2f) and A.