Immune Tolerance Induction by Integrating Innate and Adaptive Immune Regulators

A diversity of immune tolerance mechanisms have evolved to protect normal tissues from immune damage. Immune regulatory cells are critical contributors to peripheral tolerance. These regulatory cells, exemplified by the CD4(+)Foxp3(+) regulatory T (Treg) cells and a recently identified population named myeloid-derived suppressor cells (MDSCs), regulate immune responses and limiting immune-mediated pathology. In a chronic inflammatory setting, such as allograft-directed immunity, there may be a dynamic “crosstalk” between the innate and adaptive immunomodulatory mechanisms for an integrated control of immune damage. CTLA4-B7-based interaction between the two branches may function as a molecular “bridge” to facilitate such “crosstalk”. Understanding the interplays among Treg cells, innate suppressors and pathogenic effector T (Teff) cells will be critical in the future to assist in the development of therapeutic strategies to enhance and synergize physiological immunosuppressive elements in the innate and adaptive immune system. Successful development of localized strategies of regulatory cell therapies could circumvent the requirement for very high number of cells and decrease the risks associated with systemic immunosuppression. To realize the potential of innate and adaptive immune regulators for the still-elusive goal of immune tolerance induction, adoptive cell therapies may also need to be coupled with agents enhancing endogenous tolerance mechanisms

Dendritic cells, T cell tolerance and therapy of adverse immune reactions

Dendritic cells (DC) are uniquely able to either induce immune responses or to maintain the state of self tolerance. Recent evidence has shown that the ability of DC to induce tolerance in the steady state is critical to the prevention of the autoimmune response. Likewise, DC have been shown to induce several type of regulatory T cells including Th2, Tr1, Ts and NKT cells, depending on the maturation state of the DC and the local microenvironment. DC have been shown to have therapeutic value in models of allograft rejection and autoimmunity, although no success has been reported in allergy. Several strategies, including the use of specific DC subsets, genetic modification of DC and the use of DC at various maturation stages for the treatment of allograft rejection and autoimmune disease are discussed. The challenge for the future use of DC therapy in human disease is to identify the appropriate DC for the proposed therapy; a task made more daunting by the extreme plasticity of DC that has recently been demonstrated. However, the progress achieved to date suggests that these are not insurmountable obstacles and that DC may become a useful therapeutic tool in transplantation and autoimmune disease

First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: An open-label, randomised phase 2/3 trial

Background: Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods: In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30 000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings: Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6\ub75 years; IQR 2\ub78-12\ub79) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30 000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30 000 copies per mL (NNRTI-higher). Median follow-up was 5\ub70 years (IQR 4\ub72-6\ub70) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3\ub716 log10copies per mL for protease inhibitors versus -3\ub731 log10copies per mL for NNRTIs (difference -0\ub715 log10copies per mL, 95% CI -0\ub741 to 0\ub711; p=0\ub726), and -3\ub726 log10copies per mL for switching at the low versus -3\ub720 log10copies per mL for switching at the higher threshold (difference 0\ub706 log10copies per mL, 95% CI -0\ub720 to 0\ub732; p=0\ub756). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation: Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding: Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT). \ua9 2011 Elsevier Ltd