Low Numbers Of CD4 Research Articles

Clinical and microbiological assessment of patients with a long-term diagnosis of human immunodeficiency virus infection and Candida oral colonization

The objective of this study was to evaluate Candida oral colonization in human immunodeficiency virus (HlV)-infected patients undergoing long-term highly active antiretroviral therapy (ARV). The cross-sectional study included 331 HIV patients, diagnosed from 1983 to 2003. Oral swabs were performed, and Candida species were determined using ID 32C. Isolates were tested for antifungal susceptibility. Clinical and laboratory data were collected to identify the association with Candida colonization. In total, 161 Candida isolates were detected among 147 of the 331 patients (44%), independently of the time when HIV infection was diagnosed. Candida albicans strains represented 137 (85%) of the isolates, and were susceptible to all of the tested antifungal drugs. Among the non-C. albicans strains, six isolates were dose-dependently susceptible to fluconazole, nine to itraconazole, and seven to ketoconazole. The isolation of Candida was significantly higher in patients with virological failure (83/147; p 0.0002) and CD4+ T-lymphocyte counts <200 cells/mm3 (30/83; p 0.0003). Recovery of Candida in the oral cavity was independent of protease inhibitor (PI) usage (p 0.60). Colonized patients typically underwent salvage therapy (p 0.003), and had more episodes of opportunistic fungal infections (p 0.046) and malignancies (p 0.004). Oral Candida colonization in patients under ARV therapy was associated with the immunosupressed status of HIV-infected patients, i.e. low number of CD4+ T-cells per cubic millimetre, failure of ARV therapy (salvage therapy), and higher number of opportunistic infections and malignancies. Despite the fact that Pls have in vitro antifungal activity, the use of this class of antiretroviral agent did not influence the presence of Candida in the oral cavity of AIDS patients.

Human CD80/IL2 lentivirus transduced acute myeloid leukaemia cells enhance cytolytic activity in vitro in spite of an increase in regulatory CD4+ T cells in a subset of cultures.

Immunotherapeutic strategies are increasingly being explored as a method of enhancing anti-tumour immune responses in patients with acute myeloid leukaemia (AML). Regulatory CD4(+) T cells (Tregs) suppress effector T and natural killer (NK) cells and therefore pose a potential challenge to the efficacy of immunotherapy. AML cells transduced with a lentivirus expressing CD80 (B7.1) and IL2 (LV-CD80/IL2) are capable of stimulating T and NK cell cytotoxicity in vitro. This study examines the effect of CD80/IL2 modified AML cells on Treg number and function. We report a significant increase in the number of CD8(+) T cells (P = 0.046) CD3(-)CD56(+) NK cells (P = 0.028) and CD3(+)CD4(+)CD25(high)Foxp3(+) Tregs (P = 0.043) following stimulation for 7 days with allogeneic LV-CD80/IL2 AMLs. In contrast, autologous LV-CD80/IL2 AML cell cultures provide a weaker stimulation with a lower number of CD8(+) T cells (P = 0.011) and no change in NK cell or Treg numbers. However, an increase in cytotoxic CD8(+) T cells and NK cells are detected following both allogeneic and autologous LV-CD80/IL2 stimulation as demonstrated by an increase in IFN-gamma and CD107a expression. Despite the presence of increased numbers of Tregs with suppressive activity in a subset of cultures, increased lysis of unmodified AMLs was still achieved following allogeneic (day 0, 2.2%; day 7, 20.4%) and more importantly, autologous LV-CD80/IL2 culture in which AML patients had recently received intensive chemotherapy (day 0, 0%; day 7, 16%). Vaccination with LV-CD80/IL2 therefore provides a potential strategy to enhance anti-leukaemia immune responses without a concomitant stimulation of Treg-mediated inhibition of cytotoxic immunological responses.

Mucosal Immune Activation in Irritable Bowel Syndrome: Gender-Dependence and Association With Digestive Symptoms

Immune activation may be involved in the pathogenesis of irritable bowel syndrome (IBS). However, the relative magnitude of this immune component and its correlation with gender and gastrointestinal complaints in IBS patients remains poorly elucidated. We enrolled 48 IBS patients, with either diarrhea or constipation, 12 patients with microscopic colitis, 20 patients with ulcerative colitis, and 24 healthy controls. Colonic immunocytes were identified with quantitative immunohistochemistry on mucosal biopsies. Gastrointestinal symptoms were assessed using a validated questionnaire. IBS patients showed a significant 72% increase in mucosal immune cells compared to controls (P<0.001). Further analyses showed that increased immune cells were present in 50% of the IBS patients. The magnitude of the immune infiltrate in IBS was significantly lower than that of microscopic colitis or ulcerative colitis (42% and 124% increases vs. IBS, respectively; P<0.001). Compared with controls, IBS patients had increased numbers of CD3+, CD4+, and CD8+ T cells and mast cells (P<0.001). Compared to male IBS patients, female IBS patients had greater numbers of mast cells (P=0.066), but lower numbers of CD3+ and CD8+ T cells (P=0.002 and <0.001, respectively). Mucosal mast cell infiltration of IBS patients was significantly associated with abdominal bloating frequency (P=0.022) and with symptoms of dysmotility-like dyspepsia (P=0.001), but not ulcer-like dyspepsia. A large subset of IBS patients shows gender-dependent mucosal infiltration of immunocytes that correlates with abdominal bloating and dysmotility-like dyspepsia. These results provide the rationale for considering immune mechanisms as a pathophysiological component in a subset of IBS patients.

Low MHC-I density impairs the homeostatic proliferation of CD8 T cells after HSCT

We hypothesise that the modifications in the Major Histocompatibility Class I (MHC-I) expression after Hematopoietic Stem Cell Transplantation (HSCT) might impact on CD8 T cell recovery. To evaluate our proposal, we measured the number of peripheral CD8 T cells and the MHC-I expression on the monocytes from the patients who underwent allogenic or autologous HSCT. Three months after transplantation, almost all of the autologous recipients showed a high density of MHC-I and the CD8 T cell counts were within the normal range. In contrast, allogeneic recipients had low or heterogeneous expression of MHC-I and low numbers of CD8 T cells. Similar patterns were observed even after 6 to 20 months after transplantation. Recent thymic emigrants and serum levels of IL-7 and IL-15 were similar within both groups of patients. Together, our results indicate that Homeostatic Peripheral Expansion (HPE) is the main mechanism to reach the normal numbers of CD8 T cells immediately after HSCT. A high and homogenous expression of MHC-I molecules is required for an optimal HPE.

Future Targets for Immune Therapy in Colitis?

Crohn's disease and Ulcerative Colitis, collectively termed inflammatory bowel disease (IBD), are chronic inflammatory disorders of the bowel. It is generally accepted that the pathology associated with IBD is characterized by a hyper-reactive immune response in the gut wall directed against the commensal intestinal bacterial flora, and that the CD4+ T cells dominate the adaptive immune response. Chemokines are small proteins involved in the guidance of migration of immune cells during normal homeostasis and inflammation. Chemokines have been shown to play a central role in recruiting inflammatory cells to the inflamed bowel of IBD patients, making the chemokine/receptor system appealing as new therapeutic targets to sustain remission in these patients. In the severe combined immunodeficiency transfer model of colitis, which histopathologically resembles human IBD, low numbers of CD4+CD25- T cells from congenic normal mice are transplanted into immune deficient mice, which in turn develop a chronic lethal colitis within 1-2 months. By simultaneous transplantation of CD4+CD25+ regulatory T cells (Tregs) it is possible to hinder development of colitis. Thus the model is well suited for studying mechanisms underling both the effector and the regulatory components of chronic inflammation. In the current review we discuss new possible targets for immune therapy in colitis.

Prospective Phase II Study of Biologic Assignment One Vs Two Unit Umbilical Cord Blood Transplant (UCBT) in the Reduced-Intensity Conditioning Setting.

Retrospective analyses of UCBT using early historic controls show more robust graft vs leukemia effect in recipients given two-units vs one-unit. We present herein analyses from this single institution, prospective phase II clinical trial conducted 9/2003 to 5/2008 comparing 1 vs 2 unit UCBT in patients (pts) with high-risk, recurrent hematologic malignancies treated with reduced-intensity conditioning. The number of units infused in each pt was determined by biologic assignment based on the number of cells contained in the primary unit. Pts received 1 UCB unit if the cell dose was ≥ 2.5 x 10 7 nucleated cells/kg recipient weight and 2 UCB units for a minimum total combined cell dose of 1.5 x 10 7 cells/kg recipient weight if only smaller units were available. The UCB grafts were matched at ≥ 4/6 HLA loci (antigen level matching at class I A and B loci, and allele level matching class II DRB1 loci) except for 1 pt (3/6). If 2 UCB units were used they needed to be at least a 4/6 match to each other. The conditioning regimen included: Fludarabine 35 mg/m 2 /d x 5 days, cyclophosphamide 1 g/m 2 /day x 2 days, ATG 30 mg/kg/day x 2 days and single fraction TBI 200 cGy. Thirty-seven pts, 14 females, 23 males, median age 49 (range 20–71) years were enrolled. Most pts had advanced stage or high-risk hematologic malignancies; 28 pts (76%) had MDS/AML and 9 (24%) had other hematologic malignancies. Two pts underwent 2 transplants on this study after relapsing following the first UCBT. Twenty-seven pts received 1 unit and 10 pts received 2 units. The median follow up for survivors is 17.9 (range 1.2–55.9) months (mos) and median follow up for all pts is 10.1 mos. Median time to an ANC > 500/μL on 3 consecutive evaluations was 24.5 (range 12–55) days and 25 (range 13–43) days for 1 and 2 units, respectively (p=0.361). Median time to platelets > 20,000/μL without transfusion support on 3 consecutive evaluations was 38.5 (range 24–84) days and 63.5 (range 38–117) days for 1 and 2 UCB units, respectively (p=0.009). Median event-free survival (EFS) and median overall survival (OS) did not differ comparing 1 vs 2 units: 127 (range 16–1785+) days and 216 (range 16–1785+) days for 1 unit UCBT vs 92.5 (range 27– 1545+) days and 112 (range 27–1545+) days for 2 unit UCBT. The Kaplan-Meier (K-M) OS for 1 unit UCBT was 35.6% at 4 years compared to 33.3% for 2 unit UCBT (p=0.403). No statistically significant difference in K-M 4 year EFS was seen (p=0.894). At day +100, 7 pts (26%) had progressive disease or died in the 1 unit UCBT arm compared to 5 pts (50%) in the 2 unit UCBT arm. To date 51.8% of pts in the 1 unit arm have relapsed compared to 30% in the 2 unit arm (p=0.288). A total of 15/27 pts (56%) in the 1 unit UCBT arm died and 6/10 (60%) in the 2 unit UCBT arm died. Treatment-related mortality occurred in 3/10 pts in the 2 unit UCBT arm vs 2/27 in the 1 unit UCBT arm. Chimerism analyses were performed by VNTR analyses of blood mononuclear cells to confirm donor engraftment. Ten pts failed to achieve > 60% donor chimerism by day T+42, 8/26 in the 1 unit arm and 2/9 in the 2 unit arm (p=0.625). One pt died in each arm prior to T+42. Primary engraftment failure was defined by failure to restore donor or pt hematopoiesis requiring UCBT with the back up graft. Notably, 4 pts had primary and 1 pt had secondary engraftment failure in the 1 unit UCBT arm while no engraftment failures were observed in the 2 unit UCBT arm. No pts had grade 4 acute GVHD and no differences for overall incidence acute GVHD were noted comparing 1 vs 2 unit UCBT. Grade 3 acute GVHD was seen in 5/26 (19%) pts in the 1 unit UCBT arm and 3/10 (30%) in the 2 unit UCBT arm (p=0.658). Chronic GVHD was seen in 3 of 23 (3 limited) evaluable 1 unit UCBT pts and 2 of 7 (1 limited, 1 extensive) 2 unit UCBT pts. Pts who received a 2 unit UCBT had increased number of CD3+ cells (p=0.011) and total nucleated cells (TNC) (p

Two Distinct T Cell Subsets, CD4+ and CD8+CD60+, and Their Cytokines Are Required for In Vitro Induction of Human Ragweed-Specific Memory IgE Responses

CD8(+)CD60(+) T cells (80-98% CD45RO(+); 20% CD23(+)) are significantly increased in the blood of serum IgE(+) ragweed-sensitized (RS) compared with serum IgE-nonatopic humans (p = 0.001). CD8(+)CD60(+) T cells of the RS patients produced IL-2, IL-4, IL-10, IL-12, IFN-alpha. and IFN-gamma, but not IL-6 or IL-13. When their PBMC were cultured with ragweed Ag (RA), peak IgE responses occurred on day 10; none was induced with non-cross-reacting or without Ag; nonatopic PBMC did not respond to any stimulant. When either CD4(+) or CD8(+)CD60(+) T cells were depleted from RS PBMC before culture with RA, no IgE responses were induced. If purified CD4(+) T cells or low numbers of CD8(+)CD60(+) T cells were added back to the depleted PBMC, IgE responses were restored. However, higher numbers of CD8(+)CD60(+) T cells totally suppressed IgE responses. Total suppression also was obtained when RS PBMC were cultured with RA and either anti-IL-2, IL-4, IL-10, IL-12, IFN-gamma (all concentrations), or IFN-alpha (low concentrations), but not anti-IL-6 or IL-13. Higher concentrations of anti-IFN-alpha potentiated IgE responses.

Progressive multifocal leuconcephalopathy and autoimmune haemolytic anemia in chronic lymphocytic leukaemia: more than a fortuitous combination?

Progressive multifocal leuconcephalopathy and autoimmune haemolytic anemia in chronic lymphocytic leukaemia: more than a fortuitous combination?

Chronic colitis associated with HIV infection can be related to intraepithelial infiltration of the colon by CD8+ T lymphocytes

Gastrointestinal complications in AIDS patients with diarrhoea are common clinical manifestations, frequently diagnosed by colonoscopy as non-specific colitis. We retrospectively study colon biopsies diagnosed as chronic colitis associated with HIV (CCH). Biopsies were sorted as patients with AIDS (serum CD4 <200 cell/mm3) but without any clear infectious process (n = 12) and patients without HIV infection (n = 24). There are low numbers of CD4+ T lymphocytes in lamina propria of AIDS patients, but CD8+ T populations in this area appear to be similar in all studied groups, regardless of HIV infection or laboratory evidence of a specific agent. We found the clear evidence of CD8+ T cells infiltration in colonic mucosa in HIV patients with microscopic colitis. An imbalance of lymphocyte subpopulations in the colon, both in the lamina propria and epithelium, could result in an intraepithelial CD8 infiltration, involved in the pathogenesis of CCH in AIDS patients.

Both IgA subclasses are reduced in parotid saliva from patients with AIDS

Secretory IgA (SIgA), the isotypes IgA1 and IgA2, and IgM were measured by ELISA in stimulated parotid saliva from patients with AIDS (n = 16), subjects with asymptomatic HIV infection (n = 28), and HIV-seronegative healthy controls (n = 19). SIgA was significantly reduced in the AIDS group (10.4 micrograms/ml) compared with the asymptomatic HIV-infected subjects (17.1 micrograms/ml) and the controls (23.0 micrograms/ml). This decrease comprised both IgA1 and IgA2 to a similar extent on a relative basis. The SIgA decrease in AIDS patients was in striking contrast to their serum IgA level, which was significantly increased (6.9 g/l) compared with the asymptomatic HIV-infected subjects (2.9 g/l) as well as the controls (2.8 g/l). Low parotid output of SIgA in patients with HIV infection was associated with low numbers of CD4+ lymphocytes in peripheral blood as well as the presence of oral infections. The parotid output of IgM was similar in all groups. A low level of SIgA in the external secretions of patients with AIDS may well contribute to their frequent mucosal infections of opportunistic microorganisms.

Impairedin vitrosurvival of monocytes from patients with HIV infection

In vitro survival of monocytes (MO) was studied in 59 patients with HIV infection of different clinical stages. MO from 61 donors and 12 healthy seronegative homosexual men were also examined. Compared with the number of MO seeded, the percentage of adherent monocyte-derived macrophages (MDM) present after 10 days was significantly lower in patients with HIV infection than in the controls. However, the number of viable, non-adherent MO/MDM was similar in patients and controls. Our data indicate markedly decreased in vitro survival of MO from patients with HIV infection. After 10 days, the MDM population in the patient cultures was significantly less differentiated than the control cells, assessed by immunocytochemical staining with monoclonal antibodies against differentiation antigens. Reduced in vitro survival of MO/MDM was associated with low numbers of CD4+ and CD8+ lymphocytes in blood, reduced lymphocyte mitogen responses, presence of HIV p24 antigen in serum and advanced clinical stage. Decreased in vitro survival of MO/MDM may be associated with HIV replication in the cells. Although the level of HIV replication in the cultures was low as assessed by measurement of HIV p24 antigen in culture supernatants and staining of MO/MDM for HIV antigens, cytopathogenic effects of HIV or HIV products cannot be ruled out.

MMP19 Is Essential for T Cell Development and T Cell-Mediated Cutaneous Immune Responses

Matrix metalloproteinase-19 (MMP19) affects cell proliferation, adhesion, and migration in vitro but its physiological role in vivo is poorly understood. To determine the function of MMP19, we generated mice deficient for MMP19 by disrupting the catalytic domain of mmp19 gene. Although MMP19-deficient mice do not show overt developmental and morphological abnormalities they display a distinct physiological phenotype. In a model of contact hypersensitivity (CHS) MMP19-deficient mice showed impaired T cell-mediated immune reaction that was characterized by limited influx of inflammatory cells, low proliferation of keratinocytes, and reduced number of activated CD8+ T cells in draining lymph nodes. In the inflamed tissue, the low number of CD8+ T cells in MMP19-deficient mice correlated with low amounts of proinflammatory cytokines, especially lymphotactin and interferon-inducible T cell α chemoattractant (I-TAC). Further analyses showed that T cell populations in the blood of immature, unsensitized mice were diminished and that this alteration originated from an altered maturation of thymocytes. In the thymus, thymocytes exhibited low proliferation rates and the number of CD4+CD8+ double-positive cells was remarkably augmented. Based on the phenotype of MMP19-deficient mice we propose that MMP19 is an important factor in cutaneous immune responses and influences the development of T cells.

Anti-HIV Activity Mediated by Natural Killer and CD8+ Cells after Toll-Like Receptor 7/8 Triggering

We previously found that triggering TLR7/8 either by single stranded HIV RNA or synthetic compounds induced changes in the lymphoid microenvironment unfavorable to HIV. In this study, we used selective TLR7 and 8 agonists to dissect their contribution to the anti-HIV effects. While triggering TLR7 inhibited efficiently HIV replication in lymphoid suspension cells from tonsillar origin, its effect was inconsistent in peripheral blood mononuclear cells (PBMC). In contrast, triggering TLR8 showed a very prominent and overall very consistent effect in PBMC and tonsillar lymphoid suspension cells. Depletion of dendritic cells (DC), Natural killer cells (NK) and CD8+ T-cells from PBMC resulted in the reversal of TLR8 induced anti-HIV effects. Especially noteworthy, depletion of either NK or CD8+ T-cells alone was only partially effective. We interpret these findings that DC are the initiator of complex changes in the microenvironment that culminates in the anti-HIV active NK and CD8+ effector cells. The near lack of NK and the low number of CD8+ T-cells in tonsillar lymphoid suspension cells may explain the lower TLR8 agonist's anti-HIV effects in that tissue. However, additional cell-type specific differences must exist since the TLR7 agonists had a very strong inhibitory effect in tonsillar lymphoid suspension cells. Separation of effector from the CD4+ target cells did not abolish the anti-HIV effects pointing to the critical role of soluble factors. Triggering TLR7 or 8 were accompanied by major changes in the cytokine milieu; however, it appeared that not a single soluble factor could be assigned for the potent effects.These results delineate the complex effects of triggering TLR7/8 for an efficient antiviral defense. While the ultimate mechanism(s) remains unknown, the potent effects described may have therapeutic value for treating chronic viral diseases. Notably, HIV replication is blocked by TLR triggering before HIV integrates into the host chromosome which would prevent the establishment or maintenance of the latent reservoir.

Primary Study on the Reconstitution of CD4+CD25high Regulatory T Cells Early after Allogeneic Hematopoietic Stem Cell Transplantation.

Background: CD4+CD25+ regulatory T cell has been found to play an important role in suppressing allogenetic immune response and controlling GVHD recently. Our study was to explore the reconstitution of CD4+CD25high regulatory T cells early after allogeneic hematopoietic stem cell transplantation(allo-HSCT), and to evaluate its role in the development of acute Graft-versus- host disease(aGVHD)Methods :27 patients undergoing allo-HSCT were enrolled. Detect the CD4+CD25high T cells subpopulation ratios in CD4+ T lymphocytes(CD4+CD25high/CD4+)with Flow cytometry, and the expression of FOXP3 mRNA with Real-time PCR assays in the donor grafts and periperal blood frequently after transplantation(at 2 weeks,1 month,2 month,3 month post-transpant,at the onset of aGVHD,and when aGVHD was controlled.).Results:1.In without aGVHD group, the CD4+CD25high/CD4+ ratio increased significantly at 2 weeks post-transplant, and decreased later(P<0.05); the expression of FOXP3 increased significantly early after transplantation, but remained below the healthy-control level within 3 months after transplantation(P<0.05).2.In aGVHD-group, the CD4+CD25high/CD4+ ratio also increased significantly at 2 weeks post-transplant,but exhibited no decrease tendency later(P<0.05);moreover the expression of FOXP3 remained low(P<0.05),and was lower than the without-aGVHD-group at 1∼3month post-transplant(P<0.05).3.At the onset of aGVHD, the CD4+CD25+ /CD4+ and the CD4+CD25high/CD4+ ratios were both higher than the healthy control and without-aGVHD group(P<0.05),but the expression of FOXP3 were lower than that of healthy control and without-aGVHD group(P<0.05);when aGVHD was controlled, the expression of FOXP3 raised compared with that at the onset of aGVHD(P=0.025), also the CD4+CD25high/CD4+ ratio exhibited an increase tendency(P=0.050).Conlusion:1.The CD4+CD25high regulatory T cells subpopulation undergo a significant expansion early after transplantation, but its complete reconstitution is a long-term process.2.The lower number of CD4+CD25high regulatory T cells and/or their lower expression of FOXP3 gene may be related with the development of aGVHD.

HIV-1 Upregulates Intercellular Adhesion Molecule-1 Gene Expression in Lymphoid Tissue of Patients With Chronic HIV-1 Infection

Intercellular adhesion molecule (ICAM)-1 is an adhesion molecule that plays an important role in the transmission of HIV-1 to CD4+ target cells and in the decrease of these cells in lymphoid tissue (LT). Our main objective was to study ICAM-1 expression in LT from HIV-1-infected persons and to correlate this expression with LT viral load and the immunoarchitecture alteration before and after highly active antiretroviral therapy (HAART). Tonsillar LT samples from 16 patients with chronic asymptomatic HIV-1 infection were studied before initiating treatment and after 12 months of HAART. ICAM-1 protein expression was studied by immunohistochemistry in all cases, and ICAM-1 messenger RNA (mRNA) was quantified from frozen tissue in 6 patients using quantitative real-time polymerase chain reaction (PCR). LT viral load was determined by PCR. The LT immunoarchitecture, p24 immunoexpression, and CD4+ cell count were assessed from tissue sections. Before initiating HAART, there was high immunohistochemical ICAM-1 expression in follicular dendritic and endothelial cells and high ICAM-1 mRNA quantification. These findings correlated with a high LT viral load, strong p24 expression, and an effacement of LT immunoarchitecture with a low number of CD4+ cells. After HAART, there was a significant decrease of immunohistochemical and gene ICAM-1 expression. These results correlated with a significant decrease of LT viral load and p24 immunoexpression, a recovery of LT architecture, and a significant increase of CD4+ cells. HIV-1 upregulates ICAM-1 expression in LT. This finding is associated with a marked effacement of LT architecture. HAART produces downregulation of ICAM-1 expression and recovery of LT architecture by reducing LT viral load significantly.

Modeling HIV quasispecies evolutionary dynamics.

BackgroundDuring the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains.ResultsWe present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection (multiple infections at different times) or coinfection (simultaneous infection by different strains), quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate a large variety of R5 variants able to interact with chemokine receptors different from CXCR4. The decrease of CD4+ T cells, during AIDS late stage, can be described taking into account the X4-related Tumor Necrosis Factor dynamics.ConclusionThe results of this study bridge the gap between the within-patient and the inter-patients (i.e. world-wide) evolutionary processes during HIV infection and may represent a framework relevant for modeling vaccination and therapy.

Immunomodulation by costimulation blockade inhibits rejection of nerve allografts

The aim of this study was to investigate if costimulation blockade could be used to modulate the immune response, to prevent rejection, and to stimulate regeneration into nerve allografts. Nerve allografts from Balb/C mice, and isogenic nerve grafts (isografts) from C57/BL6 mice, were used to bridge a 7-mm gap of the sciatic nerve in C57/BL6 mice. Allograft recipients were treated with either a triple treatment with anti-lymphocyte function antigen-1 (anti-LFA), anti-CD40 ligand (anti-CD40L), and cytotoxic T-lymphocyte antigen 4 immunoglobulin (anti-CTLA4Ig) or isotype antibodies (placebo) at postoperative days 0, 2, 4, and 6 (intraperitoneal). After 5 or 9 days, the nerve grafts, together with the proximal and the distal nerve segments, were evaluated by histology and immunocytochemistry for inflammatory cells [CD4-positive (CD4+) and CD8-positive (CD8+) staining cells] and axonal outgrowth (neurofilaments). The immune response was inhibited by costimulation blockade with less extensive inflammation and a lower number of CD4+ staining cells in triple-treated allografts at 9 days. The regeneration rate was significantly faster in isografts (0.75 mm/day) compared with allografts with placebo treatment (0.39 mm/day), but not when compared with triple-treated allografts (0.49 mm/day). At 9 days, the axons were significantly longer in nerve isografts than in nerve allografts, irrespective of treatment. Hence, costimulation blockade neither increased the regeneration rate nor the outgrowth length in triple-treated allografts. We conclude that costimulation blockade inhibits the immune response in nerve allografts without deterring early axonal outgrowth.

No Immune Risk Profile among individuals who reach 100 years of age: Findings from the Swedish NONA immune longitudinal study

In the present NONA immune longitudinal study, we investigate the previously identified Immune Risk Profile (IRP), defined by an inverted CD4/CD8 ratio and associated with persistent cytomegalovirus infection and increased numbers of CD8+CD28− cells, relative 6-year survival and age in NONA individuals. These subjects have now reached age 92, 96, and for the first time in this study, 100 years at follow-up. A 55 year old middle-aged group was used for comparison. Immunological monitoring included the analysis of numbers of lymphocytes and neutrophils, the T-cell subsets CD3+CD4+, CD3+CD8+, CD8+CD28+, CD8+CD28−, and the CD4/CD8 ratio. Longitudinal data were analysed by multivariate analyses of variance (MANOVA) from four measurement occasions at 2-year inter-intervals. One-way ANOVA was used for cross-sectional comparisons at baseline and the 6-year follow-up. The results confirmed the importance of the IRP as a major predictor of mortality in this population of very old. Moreover, the results suggested that survival to the age of 100 years is associated with selection of individuals with an “inverted” IRP that was stable across time, i.e., maintenance of a high CD4/CD8 ratio and low numbers of CD8+CD28− cells. The results underlines the importance of a longitudinal study design in dissecting immune parameters predictive of survival and show for the first time that centenarian status is associated with avoidance of the IRP over at least the previous 6 years and probably throughout life.

Immunization With Neurofilament Light Protein Induces Spastic Paresis and Axonal Degeneration in Biozzi ABH Mice

Axonal damage is the major cause of irreversible neurologic disability in patients with multiple sclerosis. Although axonal damage correlates with antibodies against neurofilament light (NF-L) protein, a major component of the axonal cytoskeleton, the possible pathogenic role of autoimmunity to axonal antigens such as NF-L has so far been ignored. Here we show that Biozzi ABH mice immunized with NF-L protein develop neurologic disease characterized by spastic paresis and paralysis concomitant with axonal degeneration and inflammation primarily in the dorsal column of the spinal cord. The inflammatory central nervous system lesions were dominated by F4/80+ macrophages/microglia and relatively low numbers of CD4+ and CD8+ T-cells. In splenocyte cultures, proliferation to NF-L was observed in CD4+ T-cells accompanied by the production of the proinflammatory cytokine interferon-gamma. Elevated levels of circulating antibodies recognizing recombinant mouse NF-L were present in the serum, and immunoglobulin deposits were observed within axons in spinal cord lesions of mice exhibiting clinical disease. These data provide evidence that autoimmunity to NF-L protein induces axonal degeneration and clinical neurologic disease in mice, indicating that autoimmunity to axonal antigens, as described in multiple sclerosis, may be pathogenic rather than acting merely as a surrogate marker for axonal degeneration.

MDR-TB AND HIV: THE PERFECT STORM?

MDR-TB AND HIV: THE PERFECT STORM?