Using murine models, scientists from the Dana-Farber Cancer Institute (MA, USA) have studied a new subset of immune cells that may prevent the immune system from attacking an animals‘ own cells, protecting them from autoimmune diseases such as multiple sclerosis, Type 1 diabetes and lupus.
“The traditional view of the immune system is of specialized groups of cells poised to attack foreign pathogens,” said group leader, Harvey Cantor. “While that model is generally correct, we‘ve come to appreciate that the immune system, like other complex biological information systems, includes a counterbalance mechanism – a set of cells programmed to suppress the immune response. Such cells are essential to preventing excessive reactions to pathogens and misguided attacks on the body‘s own cells.”
The majority of research to date has focused on CD4+ T cells, with CD4+CD25+Foxp3+ regulatory T cells (or naturally occurring Tregs) being the best characterized and able to induce T-cell suppression and reduce inflammation. Other subsets of Treg cells exist but their functions and mechanisms of action remain elusive.
The Dana-Farber team studied a subset of cytotoxic CD8+ T cells that bind to follicular T-helper cells via a protein called Qa-1. This subset of CD8+ cells is able to inhibit the follicular T-helper cells, preventing them from interacting with B cells. No T-helper–B-cell interaction means no production of autoantibodies by B cells, thus preventing autoimmune diseases. This interaction is highly dependent on the presence of Qa-1, thus this subset of regulatory T cell is also called Qa-1-restricted T cell. Mice with abnormal Qa-1 developed a lupus-like disease, because CD8+ Treg cells could not interact with the follicular T-helper cells, leaving these cells free to help B cells to produce the lupus-causing autoantibodies.
In addition, it also turns out that the survival of CD8+ Treg cells depends on the cytokine IL-15. The findings provide a potentially powerful way of dealing with autoimmune diseases. Increasing the number of CD8+ Treg cells can suppress the autoimmune responses. On the other hand, reducing the number of these regulatory cells may boost the desired immune response in cases such as cancer vaccination.
“Experience has shown that vaccines that simply activate or expand the number of T and B cells are not likely to result in a prolonged, robust antitumor response,” explained Cantor. “The balancing mechanism within the immune system means that when more disease-fighting cells are generated, there‘s a countervailing increase in the number of immune-suppressing cells that are generated. The key is to break that loop. This work brings that goal closer.”
The research was supported by grants from the US NIH, the Lupus Research Institute and the Schecter Research Foundation. The findings were published in the September issue of the journal Nature.
Sources: Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H: Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance. Nature 467(7313), 328–332 (2010); Dana-Farber Cancer Institute, MA, USA: www.dana-farber.org
A group of researchers from Walter and Eliza Hall Institute (Australia) has shown that a protein called PU.1 is essential for the development of dendritic cells (DCs). Their findings have been published in a recent issue of the journal Immunity.
Dendritic cells are important immune cells that present foreign antigens to other immune cells such as T cells, allowing a full immune response to be mounted against the pathogens. Cancer patients who have suppressed DC function may also benefit from DC-based immunotherapies. “The problem is people don‘t know how to develop good DCs for these therapies,” said the lead author Li Wu. “By understanding how DC development is regulated, it should be possible to create different types of DC populations for therapeutic use.”
According to Wu, one of the molecules known to be important for DC development is Flt3, a cytokine receptor found on the surface of blood stem cells and DC progenitors. “Despite its importance in early blood cell development and dendritic cell development, there is surprisingly little known about how Flt3 expression is controlled,” said Wu.
The research team has shown the transcription factor PU.1 can directly bind to the Flt3 gene to regulate its expression. “PU.1 can therefore control DC development through regulating Flt3,” said Wu.
“If PU.1 is poorly regulated, there is a deficiency in the development of blood cells and leukemia can result,” said the study‘s first author, Sebastian Carotta. “To study the role of PU.1 and look at how it‘s regulated, we developed an animal model and a new in vitro system for tracing DC development from their precursors. These systems make it possible to switch off PU.1 in the precursor cells to DCs. From that we determined that loss of PU.1 completely abolished DC development.”
The authors concluded in their article: “These studies identify PU.1 as a critical regulator of both conventional and plasmacytoid DC development and provide one mechanism of how altered PU.1 concentration can have profound functional consequences for hematopoietic cell development.”
Sources: Carotta S, Dakic A, D‘Amico A et al.: The transcription factor PU.1 controls dendritic cell development and Flt3 cytokine receptor expression in a dose-dependent manner. Immunity 32(5), 628–641 (2010); Walter and Eliza Hall Institute of Medical Research, Victoria, Australia: www.wehi.edu.au
Cytheris SA (France) has announced the initiation of INSPIRE 3, a Phase II clinical trial investigating the effect of CYT107 – Cytheris‘s investigative immunomodulator, recombinant human IL-7 – in the treatment of chronically HIV-1-infected patients.
HIV primarily infects CD4+ T cells – a vital cell type of the adaptive immune system – leading to low levels of these cells. Approximately 25–30% of HIV-infected patients who receive highly active antiretroviral therapy (HAART) do not show a marked increase in their CD4+ T-cell count, despite achieving suppression of HIV viral load. These patients are referred to as immunological nonresponders (INRs).
Previous clinical trials have demonstrated that three subcutaneous injections of a new recombinant human IL-7 – CYT107 – can induce a rapid and sustained increase of CD4+ and CD8+ T cells in HIV-infected patients.
INSPIRE 3 is a multicenter, open-labeled, controlled, randomized Phase II study of CYT107 treatment at a dose of 20 µg/kg/week to restore and maintain CD4 T-cell counts above 500 cells/µl in INR patients with CD4 counts of between 101 and 350 cells/µl after at least 2 years of HAART and plasma HIV RNA below 50 copies/ml for 18 months. The study will enroll a total of 80 patients in Italy, Switzerland and South Africa.
“We are pleased to announce that the INSPIRE 3 clinical program is underway. The repeated treatment cycles of CYT107 in this study mimic the way the product will be used in the clinical setting and should trigger an improved and more prolonged immune reconstitution, a stabilization of patient CD4+ T‑cell counts above 500/µl, and a decrease of the markers of activation/inflammation,” said Michel Morre, president and chief executive officer of Cytheris. “The safety and efficacy results obtained in this trial will contribute to the clinical profile of CYT107 as a potentially important new option for HIV patients and will also serve to define the clinical end points in subsequent pivotal therapeutic studies.”
The primary objective of INSPIRE 3 is to investigate the biological activity and safety of repeated cycles of CYT107 at 20 µg/kg/week over 2 weeks, for a maximum of four cycles within 21 months and a maximum of three cycles within 12 months.
“In the INSPIRE 3 trial the goal is to establish the safety and biological activity of repeated cycles of CYT107 administered in a way that will optimize the chances that INR patients will be able to remain above 500 CD4+ T cells/µl during the study period,” said Giuseppe Tambussi, head of Experimental Therapies Unit, Infectious Disease Clinic, San Raffaele Hospital (Milan, Italy) and principal investigator/study chairman for the trial. “This is a key prerequisite for undertaking studies aimed at demonstrating the clinical efficacy of such a therapeutic regimen.”
Besides HIV infection, Cytheris is currently conducting multiple international investigations of IL-7 in other diseases, including hepatitis B and C, idiopathic CD4 lymphocytopenia and cancer.
Source: Cytheris SA, France: www.cytheris.com