Programmed death (PD)-1 molecule and its ligand PD-L1 distribution among memory CD4 and CD8 T cell subsets in human immunodeficiency virus-1-infected individuals.

Human immunodeficiency virus (HIV)-1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti-HIV-1-specific responses: programmed death (PD)-1 molecule and its ligand PD-L1 are negative regulators of T cell activity and their expression is increased during HIV-1 infection. This study examines correlations between T cell maturation, expression of PD-1 and PD-L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV-1(+) and 17 uninfected individuals were phenotyped for PD-1 and PD-L1 expression on CD4(+) and CD8(+) T cell subsets. The effect of PD-1 and PD-L1 blockade on proliferation and interferon (IFN)-gamma production was tested on eight HIV-1(+) patients. Naive (CCR7(+)CD45RA(+)) CD8(+) T cells were reduced in HIV-1 aviraemic (P = 0.0065) and viraemic patients (P = 0.0130); CD8 T effector memory subsets [CCR7(-)CD45RA(-)(T(EM))] were increased in HIV-1(+) aviraemic (P = 0.0122) and viraemic (P = 0.0023) individuals versus controls. PD-1 expression was increased in CD4 naive (P = 0.0496), central memory [CCR7(+)CD45RA(-) (T(CM)); P = 0.0116], T(EM) (P = 0.0037) and CD8 naive T cells (P = 0.0133) of aviraemic HIV-1(+) versus controls. PD-L1 was increased in CD4 T(EMRA) (CCR7(-)CD45RA(+), P = 0.0119), CD8 T(EM) (P = 0.0494) and CD8 T(EMRA) (P = 0.0282) of aviraemic HIV-1(+)versus controls. PD-1 blockade increased HIV-1-specific proliferative responses in one of eight patients, whereas PD-L1 blockade restored responses in four of eight patients, but did not increase IFN-gamma-production. Alteration of T cell subsets, accompanied by increased PD-1 and PD-L1 expression in HIV-1 infection contributes to anergy and impaired anti-HIV-1-specific responses which are not rescued when PD-1 is blocked, in contrast to when PD-L1 is blocked, due possibly to an ability to bind to receptors other than PD-1.

Immune modulation and reconstitution of HIV-1-specific responses: novel approaches and strategies.

Efficacious protection for future generations from HIV-1 infection through the development of prophylactic vaccines is the best hope for the millions of individuals living with the threat of HIV-1 infection. Advances in the development of non-curative chemotherapy for those already infected have changed the course of the epidemic for those with access to the drugs. However in the ten years since the advent of highly active anti-retroviral therapy, the expectancy of curative chemotherapy has been quashed, and the constant need for a next generation of drugs is evident. As our understanding of HIV-1 pathogenesis increases, it is becoming apparent that novel approaches and strategies will be required to halt the global progression of HIV-1. Immune-based therapies are being considered in the context of effective antiretroviral therapy. Such immune-based therapy must allow the induction or regeneration of HIV-1-specific T-cell responses with the potential to control viremia and purge viral reservoirs. Studies of therapy substitution, treatment interruption, therapeutic vaccines and/or cytokines and/or hormones have been carried out and are briefly summarised in this review.

Inflammation-induced modulation of cellular galectin-1 and -3 expression in a model of rat peritonitis.

OBJECTIVE AND DESIGN: To investigate the effect of galectin-1 (Gal-1) and -3 (Gal-3) on leukocyte migration and analyze the expression of both galectins in inflammatory cells using a model of rat peritonitis. MATERIAL OR SUBJECTS: Sprague-Dawley rats (n = 4 per group). TREATMENT: Peritonitis was induced in animals through intraperitoneal injection of carrageenin (1.5 mg/kg) and rat mesenteries were analyzed at different time points (0, 4, 24 and 48h). For pharmacological treatment, rats received intravenous injection of Gal-1 or -3 (3microg/kg) followed by carrageenin. METHODS: Western blotting and immunoelectron microscopy analysis. Statistical analysis was performed using ANOVA followed by Bonferroni test. RESULTS: Pharmacological treatment with Gal-1, but not Gal-3, inhibited (approximately 50 %) leukocyte recruitment into the peritoneal cavity at 4 h time-point. In this early phase, immunogold staining of mesenteries showed a diminished Gal-3 expression in degranulated mast cells and Gal-1 in transmigrated neutrophils (approximately 20 % reduction compared to intravascular cells). In the later phases (24 and 48h), leukocyte turnover was associated with augmented Gal-1 expression in neutrophils and macrophages and Gal-3 in mast cells and macrophages. CONCLUSIONS: These results point to a balanced expression of cell-associated-Gal-1/Gal-3 and might impact on the development of new therapeutic strategies for inflammatory diseases.

Adrenalitis in the non-obese diabetic mouse.

The non-obese diabetic (NOD) mouse is a model of spontaneous type-1 diabetes used in the field of diabetes research. This study looked at the adrenal glands of NOD and control mice both indirectly in vivo for hormone secretion, and directly in vitro for histological examination. Adrenal glands were taken from NOD mice, of both sexes, at different ages and corticosterone and adrenocorticotropic hormone (ACTH) plasma levels evaluated by radioimmunoassay. There was evidence of lymphocytic infiltration of the adrenal glands, which however, was not accompanied by changes in corticosterone levels. There was a reduction in ACTH levels with age (R2 = 0.98). Mice from other strains (TFW, CBA and Balb/c) showed no lymphocytic infiltration in the adrenal glands and had lower levels of corticosterone than NOD mice of similar ages, but the differences were not significant. In conclusion, since the NOD mouse shows histological signs of adrenalitis, thyroiditis, sialitis and parathyroiditis, this animal can be regarded as a model to investigate mechanisms involved in diffuse lymphocytic infiltration of peripheral endocrine glands (polyendocrine autoimmunity). In addition, if diabetes in the NOD mouse is the result of a polyendocrine disorder rather than a process specific for diabetes, then this finding may have implications for attempts to prevent type-1 diabetes in humans.

Incomplete Freund's adjuvant reduces diabetes in the non-obese diabetic mouse.

As the study of type 1 diabetes moves towards preventive therapy, the role of adjuvants needs to be addressed. Incomplete Freund's adjuvant (IFA) is thought of as "immunologically inert" as, unlike complete FA (CFA), it has no components designed to provoke an immune response. We investigated the effect of IFA as an immunomodulator on the disease process leading to type 1 diabetes in the non-obese diabetic (NOD) mouse. 24 NOD mice were injected intradermally (i.d.) at 8 and 12 weeks of age with a 1:1 mixture of IFA and saline; 24 controls received saline alone. Splenocytes were tested against antigens thought to be involved in the disease process, namely insulin, a GAD peptide, a beta-casein peptide, a Glut-2 peptide and concanavalin A (ConA) as a non-specific antigen. In the IFA experiment diabetes incidence was 13% compared to 38% in the controls (p < 0.05). In vitro, splenocytes from IFA treated animals showed non-specific immunosuppression with ConA (p < 0.01), whereas the response to 1-casein and Glut-2 was raised in IFA treated animals with respect to controls. ELISA using supernatants from IFA treated animals, showed a typical Th2 cytokine pattern, whereas controls showed a Th1 pattern. In conclusion, IFA alone can reduce diabetes incidence in the NOD mouse apparently by modulating the immune response towards beta-cell related specific antigens. As IFA has been adopted as an adjuvant in preventive trials in the NOD mouse, this might have implications for the interpretation of previous and future results.