Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mice

Background Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine. Methods Fusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients’ cells as well as transfected A20 cells. Results DNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient’s Id as compared with non targeted control vaccines. Anti–Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients’ V regions were not tumorigenic in mice, preventing tumor challenge experiments. Conclusions These findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs

Cardiorespiratory fitness on a treadmill in an adult cystic fibrosis population

Objectives: (1) To describe the cardiorespiratory fitness (CRF) in an adult cystic fibrosis population related to sex and age, (2) to evaluate the cause of low CRF and (3) to study the association between peak oxygen uptake (VO2peak) and forced expiratory volume in 1 s (FEV1). Methods: A total of 204 cardiopulmonary treadmill exercise tests (CPETs) performed by 116 patients were included. VO2peak, gas exchange, heart rate, oxygen saturation and ventilatory variables were measured. A low CRF was defined as a VO2peak <80% of predicted, ventilatory limitation was defined as a breathing reserve <15%, exercise hypoxaemia was defined as an oxygen saturation <88% and ventilation-perfusion mismatch was defined as a minute ventilation/ventilatory equivalent for carbon dioxide slope ≥34. In patients who had performed three or more CPETs, the annual change in FEV1 and VO2peak were calculated using linear regression. Results: The VO2peak was 40.6±11.5 and 35.2±8.9 mL kg−1 min−1, which was 87±23 and 93±20 in percentage of predicted for men and women, respectively. VO2peak was moderately affected by age, for men (r=−0.36, p<0.001) and women (r=−0.53, p<0.001), respectively. In 45 of 101 tests where CRF was low, no cardiorespiratory limiting factors were identified. The correlation coefficient between VO2peak and FEV1 was r=0.64 (p<0.001). In participants with a low CRF, FEV1 ranged from 20% to 112% of predicted. Conclusions: The correlation between VO2peak and FEV1 was moderate. The majority of the tests resulted in a VO2peak within normal limits. Interestingly, 44% of the tests with a low VO2peak could be explained by deconditioning. Thus, exercise therapy may be beneficial for these patients

Cardiorespiratory fitness on a treadmill in an adult cystic fibrosis population

Objectives (1) To describe the cardiorespiratory fitness (CRF) in an adult cystic fibrosis population related to sex and age, (2) to evaluate the cause of low CRF and (3) to study the association between peak oxygen uptake (VO 2 peak) and forced expiratory volume in 1 s (FEV 1 ). Methods A total of 204 cardiopulmonary treadmill exercise tests (CPETs) performed by 116 patients were included. VO 2 peak, gas exchange, heart rate, oxygen saturation and ventilatory variables were measured. A low CRF was defined as a VO 2 peak &lt;80% of predicted, ventilatory limitation was defined as a breathing reserve &lt;15%, exercise hypoxaemia was defined as an oxygen saturation &lt;88% and ventilation-perfusion mismatch was defined as a minute ventilation/ventilatory equivalent for carbon dioxide slope ≥34. In patients who had performed three or more CPETs, the annual change in FEV 1 and VO 2 peak were calculated using linear regression. Results The VO 2 peak was 40.6±11.5 and 35.2±8.9 mL kg −1 min −1 , which was 87±23 and 93±20 in percentage of predicted for men and women, respectively. VO 2 peak was moderately affected by age, for men (r=−0.36, p&lt;0.001) and women (r=−0.53, p&lt;0.001), respectively. In 45 of 101 tests where CRF was low, no cardiorespiratory limiting factors were identified. The correlation coefficient between VO 2 peak and FEV 1 was r=0.64 (p&lt;0.001). In participants with a low CRF, FEV 1 ranged from 20% to 112% of predicted. Conclusions The correlation between VO 2 peak and FEV 1 was moderate. The majority of the tests resulted in a VO 2 peak within normal limits. Interestingly, 44% of the tests with a low VO 2 peak could be explained by deconditioning. Thus, exercise therapy may be beneficial for these patients

Open Access

Targeted DNA vaccines eliciting crossreactive anti-idiotypic antibody responses against human B cell malignancies in mic

Chronic Lymphocytic Leukemia Cells Are Activated and Proliferate in Response to Specific T Helper Cells

There is increasing interest in the chronic lymphocytic leukemia (CLL) microenvironment and the mechanisms that may promote CLL cell survival and proliferation. A role for T helper (Th) cells has been suggested, but current evidence is only circumstantial. Here we show that CLL patients had memory Th cells that were specific for endogenous CLL antigens. These Th cells activated autologous CLL cell proliferation in vitro and in human → mouse xenograft experiments. Moreover, CLL cells were efficient antigen-presenting cells that could endocytose and process complex proteins through antigen uptake pathways, including the B cell receptor. Activation of CLL cells by Th cells was contact and CD40L dependent. The results suggest that CLL is driven by ongoing immune responses related to Th cell–CLL cell interaction. We propose that Th cells support malignant B cells and that they could be targeted in the treatment of CLL