According to scientists at the University of Pittsburgh School of Medicine (UPSM; PA, USA), early immunization using a mucin (MUC) 1-based vaccine might delay the onset of inflammatory bowel disease (IBD), as well as preventing colon cancer development.
Patients with chronic inflammatory diseases tend to have a higher risk for developing cancers at the inflamed sites. However, the roles played by different components of the immune system in these conditions are not fully understood. Few investigations have focused on chronic inflammation-associated antigens and their potential as vaccine antigens for these conditions.
The UPSM team used a new transgenic mouse model (IL-10-knockout mice crossed with MUC1-transgenic mice) that had MUC1-positive colitis developing into colitis-associated colon cancer (CACC). MUC1 is a self-antigen that is altered and overexpressed in several cancers, including CACC.
The team vaccinated a group of mice with MUC1 protein and compared IBD development and progression to CACC in these animals with control mice that received no vaccine. They found that “vaccination against MUC1 delays IBD and prevents progression to CACC.” Vaccinated mice showed less inflammation of the colon tissue and no indication of CACC, while almost half of control animals had abnormal tissues and two developed CACC at the end of the experiment.
“Our experiments indicate that boosting the immune response against this protein early in the disease can delay IBD development, control inflammation and thereby reduce the risk of future cancers,” said senior author Olivera Finn, professor and chair, Department of Immunology at UPSM. “These findings suggest also that the early stages of chronic inflammation might be considered a premalignant condition.”
One explanation is that MUC1-specific immune responses (both antibodies and cytotoxic T cells) help to remove MUC1-positive cells from the colon. Another possible mechanism is ‘the change in the local and the systemic microenvironments. Compared with IBD in vaccinated mice, IBD in control mice is dominated by larger numbers of neutrophils in the colon and myeloid-derived suppressor cells in the spleen, which can compromise adaptive immunity and facilitate tumor growth.‘
“The MUC1 vaccine seems to change the local environment from one that promotes cancer development to one that inhibits it,” said Finn. “Certain immune cells that we usually see in the inflamed colon aren‘t present, and that could make the surroundings less friendly for potentially cancerous cells that also are directly targeted by the vaccine for destruction.”
The new findings imply that IBD patients may benefit from the MUC1 vaccine at an early stage of their disease. The findings were published in Cancer Prevention Research, a journal of the American Association for Cancer Research.
Sources: Beatty PL, Narayanan S, Gariepy J, Ranganathan S, Finn OJ: Vaccine against MUC1 antigen expressed in inflammatory bowel disease and cancer lessens colonic inflammation and prevents progression to colitis-associated colon cancer. Cancer Prev. Res. DOI: 10.1158/1940-6207.CAPR-09-0194 (2010); University of Pittsburgh School of Medicine, PA, USA: www.upmc.com
In a recent online publication of Nature Immunology, scientists from the Program in Cellular and Molecular Medicine and the Immune Disease Institute (PCMM/IDI) at Children‘s Hospital Boston (MA, USA) have shown that resident dendritic cells (DCs), but not macrophages, are vital for inducing an antibody response against influenza viruses.
Sinus-lining macrophages play a critical role in limiting the spread of influenza viruses by capturing the viruses and presenting viral antigens to cells of the adaptive immune system, especially cytotoxic T cells, that target and destroy virus-infected cells. A similar pathway has been assumed for macrophages in presenting viral antigens to B cells, which will produce virus-specific antibodies that neutralize any circulating viruses.
PCMM/IDI researchers, led by Michael Carroll, in collaboration with scientists from the Dana Farber Cancer Institute and Harvard Medical School (MA, USA), injected an influenza vaccine into mice and focused on what happened to inactivated influenza viruses within the vaccine inside the mouse‘s lymph nodes.
“We‘re trying to break down this black box that we know as the lymph node, and identify the different cells that are there, how they interact with each other and what the general rules are,” said Carroll. “Then, you can begin to manipulate it to improve vaccines and immune responses.”
The scientists tracked fluorescence-tagged H1N1 influenza viruses and found that most viruses were captured by macrophages, preventing the viruses from spreading. However, these macrophages did not present viral antigens to B cells for antibody production. Instead, viral antigens were presented to B cells by resident DCs, a poorly understood group of immune cells. The same result was observed in macrophage-depleted mice, in which antibodies against influenza were still produced without the need for macrophages.
To confirm this, the researchers injected mice with an inhibitor that blocks specific receptors on resident DCs. B cells in these mice were unable to produce antibodies in the presence of macrophages. They concluded that “DCs residing in the lymph node medulla use the lectin receptor SIGN-R1 to capture lymph-borne influenza virus and promote humoral immunity. Thus, our results have important implications for the generation of durable humoral immunity to viral pathogens through vaccination.”
“The government is putting a lot of money into vaccine development,” said Carroll. “A lot of people are thinking about how to target vaccines, and this kind of information will tell us what cell type we would want to target.”
“This is the first clear definition of what the resident DCs are doing,” said Carroll. The researchers believe that future designs of influenza vaccines that target these cells would enhance the vaccine effectiveness.
Carroll‘s group will now look into immune pathways that may be critical for immune responses against Streptococcus pneumoniae, a major causal agent of diseases such as pneumonia, meningitis and middle ear infections.
Sources: Gonzalez SF, Lukacs-Kornek V, Kuligowski MP et al.: Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes. Nat. Immunol. DOI: 10.1038/ni.1856 (2010); Children‘s Hospital Boston, MA, USA: www.childrenshospital.org
Researchers from the University of Pittsburgh Schools of the Health Sciences (PA, USA) might have discovered the key to a better immune response again HIV vaccines. In their recent publication in the journal PLoS ONE, they have revealed new insights into the role that regulatory T cells (Tregs) play in suppressing the immune response against HIV and suggested that controlling Treg function might improve immune responses to HIV vaccines.
Regulatory T cells are essential in keeping immune responses under control and preventing the body‘s immune system from attacking the body itself. Unwanted immune responses, such as those seen in autoimmune diseases, are controlled by Tregs. However, Tregs may also suppress desirable immune responses, as in the case of therapeutic vaccines against chronic infections (e.g., HIV) or cancers.
The researchers hypothesized that “therapeutic vaccination against HIV-1 can increase the frequency and suppressive function of regulatory, CD4+ T cells (Treg), thereby masking enhancement of HIV-1-specific CD8+ T-cell response.” They tested the hypothesis by investigating the immune responses from seven HIV-1-infected individuals who had received a dendritic cell-based HIV vaccine in a previous Phase I clinical trial.
Regulatory T cells from cryopreserved blood samples of these patients were depleted, and the polyfunctional CD8+ T-cell response (which is believed to be essential for the clearance of HIV) was determined following in vitro stimulation with HIV-1 Gag peptide or negative controls (staphylococcal enterotoxin B or medium only).
“When we removed Treg from blood cells, we found a much stronger immune response to the vaccine, giving us insight into how we can develop more effective HIV vaccines,” said the study‘s senior author Charles Rinaldo Jr, professor and chairman, Department of Infectious Diseases and Microbiology at the University of Pittsburgh‘s Graduate School of Public Health. “Treg normally shuts down CD8 responses once the infection has been controlled, but in this case it appears to be putting on the brakes early and possibly limiting the vaccine‘s ability to do its job effectively.”
The researchers found that “Treg depletion increased the polyfunctionality of the total vaccine response … with a [more than twofold] increase in the percentage of CD8+ T cells producing multiple immune mediators. In contrast, depletion of Treg did not enhance polyfunctional T-cell response to staphylococcal enterotoxin B, implying specificity of suppression to HIV-1 Gag.”
“We know how to treat HIV, but are still learning how to use immunotherapy strategies to completely flush it out of the body,” added Bernard Macatangay, assistant director, University of Pittsburgh Immunology Specialty Laboratory and the study‘s lead author. “Our findings show Treg plays an important role, but we need to figure out how to maintain the right balance by getting around these cells without blocking them completely.”
The findings imply that controlling Tregs may be critical in obtaining a desirable immune response against HIV, and that the role of Tregs should be taken into account in future HIV vaccine trials.
Sources: Macatangay BJC, Szajnik ME, Whiteside TL, Riddler SA, Rinaldo CR: Regulatory T cell suppression of Gag-specific CD8+ T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PLoS ONE 5(3), E9852 (2010); University of Pittsburgh Schools of the Health Sciences, PA, USA: www.upmc.com
Researchers at St Jude Children‘s Research Hospital (TN, USA) have demonstrated that Nlrp3, a protein already linked to an array of human inflammatory immune diseases, is involved in protecting the intestinal tract from colitis.
Colitis is a chronic inflammatory bowel disease with an estimated prevalence in the USA of 246 cases per 100,000 people/year. Inflammation in the lining of the large intestine and rectum leads to abdominal pain, diarrhea, bleeding and weight loss.
Nlrp3 is involved in the anchoring of the Nlrp3 inflammasome, a multiprotein complex involved in producing the cytokine IL-18. The team at St Judes, led by Thirumala-Devi Kanneganti, demonstrated that Nlrp3 inflammasome-produced IL-18 triggered the production of epithelial cells in the colon. These helped to compensate for those damaged or destroyed by colitis and enabled mice to maintain a healthy colon. The group also demonstrated the temporal and spatial location of these beneficial events; the Nlrp3 inflammasome is activated in the epithelial cells and produced IL-18 in response to colitis. The team believes that the identification of the specific pathway activated in the epithelial cells has the potential to advance the development of therapeutics for colitis.
“This paper provides the basis for more effective, potentially disease-modifying approaches to treatment,” said Kanneganti of her teams work. “I believe if we target molecules that are part of the innate immune response we can find cures for many diseases, including cancer.”
The team started their research into Nlrp3 and colitis after patients with Crohn‘s disease, another inflammatory bowel disease, were found to only have low levels of this protein.
Developing their research, Kanneganti and colleagues established that IL-18 is required to protect the colon from colitis and saw that, when injected into mice lacking the molecule, colitis symptoms were eased.
Sources: St Jude Children‘s Hospital, TN, USA: www.stjude.org; National Digestive Disease Information, MD, USA: http://digestive.niddk.nih.gov