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Description: Co-hosts Ryan Piansky, a graduate student and patient advocate living with eosinophilic esophagitis (EoE) and eosinophilic asthma, and Holly Knotowicz, a speech-language pathologist living with EoE who serves on APFED's Health Sciences Advisory Council, interview Dr. Wayne Shreffler, Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital. Dr. Shreffler is also an investigator at The Center for Immunology and Inflammatory Disease and The Food Allergy Science Initiative. His research is focused on understanding how adaptive immunity to dietary antigens is both naturally regulated and modulated by therapy in the context of food allergy. This interview covers the results of a research paper on The Intersection of Food Allergy and Eosinophilic Esophagitis, co-authored by Dr. Shreffler. Disclaimer: The information provided in this podcast is designed to support, not replace the relationship that exists between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.   Key Takeaways: [:50] Co-host Ryan Piansky introduces the episode, brought to you thanks to the support of Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron. Ryan introduces co-host, Holly Knotowicz.   [1:15] Holly introduces today's topic, the intersection of food allergy and eosinophilic esophagitis.   [1:26] Holly introduces today's guest, Dr. Wayne Shreffler, Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital and an investigator at The Center for Immunology and Inflammatory Disease and The Food Allergy Science Initiative.   [1:43] Dr. Shreffler's research is focused on understanding how adaptive immunity to dietary antigens is both naturally regulated and modulated by therapy in the context of food allergy.   [1:54] Holly welcomes Dr. Shreffler to Real Talk. When Holly moved to Maine, she sent her patients to Dr. Shreffler at Mass General.   [2:25] Dr. Shreffler trained in New York on a Ph.D. track. He was interested in parasitic diseases and the Th2 immune response. Jane Curtis, a program director at Albert Einstein College of Medicine, encouraged him to consider MD/PhD programs. He did.   [3:31] Jane Curtis connected him to Hugh Sampson, who was working with others to help understand the clinical prevalence of food allergy and allergens.   [3:51] As a pediatric resident, Dr. Shreffler had seen the burden of allergic disease, caring for kids in the Bronx with asthma. His interest in Th2 immunity, the clear and compelling unmet clinical need, and the problem of food allergy guided his career.   [4:31] Dr. Shreffler's wife has food allergies and they were concerned for their children. Fortunately, neither of them developed food allergies.   [5:21] Dr. Shreffler thinks the food allergy field has a lot of people who gravitate toward it for personal reasons.   [5:53] Food allergy is an adverse response to food that is immune-mediated. There is still uncertainty about this but Dr. Shreffler believes that a large percentage of patients with EoE have some triggers that are food antigens.   [6:27] The broad definition of food allergy would include things like food protein-induced enterocolitis syndrome (FPIES).   [6:47] The way we use the term food allergy in the clinic, there are two forms: IgE-mediated allergies and non-IgE-mediated allergies, including EoE.   [7:40] Some patients have food-triggered eczema, some have FPIES.   [8:04] In 2024, Dr. Shreffler and Dr. Caitlin Burk released a paper that looked at the triggers of EoE, particularly the intersection of IgE-mediated food allergy and EoE.   [8:41] Dr. Caitlin Burk joined the group as they were publishing papers on IG food allergy and EoE. It was a moment where things unexpectedly came together.   [9:17] Adaptive immunity to food proteins comes from antibodies that cause milk allergy, egg allergy, peanut allergy, or multiple allergies. The IgE has specificity.   [9:40] T cells also are specific to proteins. They express a host of receptors that recognize almost anything the immune system might encounter. They have a long memory like B-cells.   [10:09] The overlap in these two threads of research was regarding a population of T cells that are important for mediating chronic inflammation at epithelial sites, including the gut.   [10:36] These T cells have been described in the airways in asthma, in the skin in eczema, and the GI tract. Researchers years ago had also described them as being associated with IgE food allergy. People with IgE food allergies avoid allergens.   [11:13] T cells, being associated with chronic allergic inflammation, now being associated with food allergies which are not having chronic exposures to the allergen, was interesting and surprising.   [11:30] Dr. Shreffler and his group found the T cell subset in patients who don't do well with Oral Immunotherapy (OIT) and patients who have EoE with immediate symptoms.   [12:01] Dr. Shreffler notes differences. There are immediate symptoms of IgE food allergy. There is a subset of patients with EoE who have immediate symptoms that are not fully understood. Maybe IgE plays a role there.   [12:28] There are different mechanisms for how symptoms are caused and so different ways of making a diagnosis. A food allergy with an IgE antibody can be measured through skin tests and blood tests. This can help identify which foods are the trigger.   [12:57] This common T cell subset that we see in EoE and food allergy, helps to explain why IgE alone is not always a very specific marker for identifying people who will have immediate reactions when they're exposed to the food.   [13:17] For patients who react at low levels, it's not just that they have more or better IgE but they also have an expansion of these T cells that are common between EoE and other chronic forms of allergy and IgE food allergy.   [13:41] There's a lot to learn that might be relevant for patients about this T cell subset.   [14:23] These T cells are a specific subset of the group of Th2 T cells, which are a subset of all CD4 T cells. Some CD4 T cells are important for responding to viruses and tumors. Others are important for responding to outside allergens.   [15:01] In an allergy or a parasite infection, Th2 T cells are important. There is a subset of T cells that is driven by repetitive and chronic exposure to the triggering protein, antigen, or allergen.   [15:47] Most antigens are proteins that trigger an immune response. An antigen that elicits an allergic response is an allergen. [16:30] A food trigger is a protein antigen that is an allergen. In IgE, food allergies, milk, and eggs are prevalent triggers early in life. For reasons not well understood, a lot of people outgrow them. In older patients, peanut and tree nut allergies are prevalent.   [17:01] In EoE, milk is one of the most common dietary triggers into adulthood. Some patients with IgE allergy to milk can tolerate it if it's well cooked. Patients with EoE are less likely to be able to get away with regular and ongoing exposure to milk protein.   [17:54] Milk, eggs, and nuts are common triggers in both conditions. There can also be rare food allergy triggers. That's part of the early evidence that the adaptive immune response was likely to be involved. It can be so specific for some people to rare things.   [18:20] Hallmarks of something being immune-mediated are that it is reproducibly demonstrable as a trigger. It's going to be long-lived. It's going to be generally relatively small amounts. The immune system is good at detecting small exposures.   [19:07] EoE is tricky because there's not that clear and easy temporal association between an offending allergen exposure for most people and their symptoms. People don't associate the symptoms with the triggers.   [20:14] A history of having blood in the stools can be milk-allergen-driven and was associated with a diagnosis of EoE in those kids when they're older.   [20:26] There are a lot of commonalities in the allergens but it's not always obvious clinically.   [22:40] A challenge in diagnosing EoE is that providers have to be on guard against their biases. They have to give a patient good advice. In EoE there is no test to identify triggers, except rigorous introduction, elimination, reintroduction, and endoscopies.   [24:18] For some of Dr, Shreffler's patients, it becomes less important to know their dietary triggers. They gravitate toward an approved form of treatment that may, if successful, allow them to have a more normal diet because of effective medication.   [24:50] Dr. Shreffler thinks there are other triggers, including pollens. There is evidence of seasonality of active EoE in patients shown to have allergic sensitization to pollens. That's indirect evidence. If the body is making IgE, it's likely making other responses.   [25:32] There are questions about how large the population of patients is who have EoE that may be more intrinsically than extrinsically driven because of genetic variations.   [25:54] Dr. Shreffler believes that EoE in some patients is allergen-driven and in some patients EoE is food-driven. Food is a trigger for the majority of pediatric patients and a large percentage of adult patients but not necessarily the exclusive trigger.   [27:04] If a patient is motivated to learn what dietary triggers may be at play, Dr. Shreffler often makes assessments outside of pollen season for allergens to which the patient has demonstrated positivity.   [28:09] Looking at the epidemiology, both EoE and food allergy are atopic disorders. You see an increased prevalence of asthma, hay fever, eczema, and even allergic proctocolitis in infancy. You see an enrichment of one disorder to another.   [28:29] The overlap of food allergy to EoE is stronger than you might expect. About 30 to 40% of patients with EoE will also have IgE food allergy. A higher rate will have IgE positivity, whether or not that food is a trigger of immediate symptoms.   [28:48] Patients with food allergies are about four times more likely to have EoE than the general population. That's a stronger association than the risk of eczema or other atopic conditions to EoE.   [30:09] There are differences between IgE food allergy and EoE. The presence of IgE gives a useful tool for identifying the food trigger in food allergy, but not in EoE. Identifying rare triggers in EoE patients is done by clinical observation.   [31:46] Epinephrine and antihistamines are not useful in treating EoE. Blocking IgE with Omalizumab has not been effective in trials in treating EoE. PPIs, topical steroids, and dupilumab are helpful for many EoE patients.   [32:38] Dupilumab has been evaluated a bit in food allergy in combination with OIT, and there was no statistically significant benefit from dupilumab in food allergy.   [33:25] A group in Pennsylvania has been evaluating epicutaneous immunotherapy as a modality to treat EoE. It's also being evaluated for IgE food allergy. Dr. Shreffler thinks it's something to keep an eye on.   [33:40] The oral route for immunotherapy can drive EoE for patients. As they become less sensitive from an immediate reactivity viewpoint, a significant percentage of patients develop GI symptoms. This has also been observed with sublingual therapy.   [34:14] Iatrogenic EoE, caused by the treatment, may resolve on the cessation of the immunotherapy treatment.   [36:25] Dr. Shreffler says in some cases, the shared decision is a decision where he has a strong evidence-based opinion. In some cases, there's a lot more room for a range of clinical decisions that could be equally supported by what we know right now.   [36:57] We've said that EoE is a contraindication for OIT. There is a shift happening. Dr. Shreffler sits with families and has a conversation about restricting diet or trying chronic therapy and keeping an ad-lib diet.   [37:38] What about doing the same thing by treating the immediate-type food allergy with chronic allergen exposure and then ameliorating the effects of EoE if it emerges, with another therapy? A hundred providers would have a diversity of responses.   [38:19] When there is a history of EoE in a family, Dr. Shreffler advocates for getting a baseline scope. It becomes an important “ground zero.”   [38:28] The goal is to have less invasive ways to monitor these conditions.   [39:32] Chronic inflammation, which is the hallmark of EoE, is well-targeted by therapies like PPIs and steroids. Steroids don't help with IgE-related food allergies. They're not effective at blocking the IgE-driven immediate response.   [41:13] Until recently, IgE food allergy has only been managed with avoidance. We have some other tools now. Xolair is not effective in EoE but is effective in two-thirds to three-quarters of patients with immediate-type food allergies for preventing anaphylaxis.   [41:45] Dr. Shreffler refers to an upcoming study on the effectiveness of Xolair in treating people with food allergies. Those who were able to tolerate a minimum amount were allowed to begin consuming allergen. We'll get insight into how those patients did.   [43:08] Food-induced immediate response of the esophagus (FIRE) is immediate discomfort with exposure to some allergens. Dr. Shreffler explains it. Data supports that these patients are experiencing an IgE-mediated but local response to those triggers.   [44:59] If FIRE is IgE-mediated, it may be that Xolair would help suppress it in these patients. It's worth looking at Xolair for this subset of EoE patients.   [45:20] Ryan invites any listeners who want to learn more about FIRE to check out episode #34 with Dr. Nirmala Gonsalvez.   [45:37] In the paper, Dr. Shreffler wrote about what he hopes will be the practical usefulness of the finding, the intersection between IgE food allergy and EoE.   [45:56] A subset of Th2 T cells express a protein called GPR15. It appears to be a marker for the subset of cells that are playing a role in the EoE.   [46:36] Caitlin Burk's work now is looking at their activation status in active disease and post-diet elimination and remission. She is developing a data set that is leading us toward the possibility of focusing on that cell subset and techniques to adopt in clinics.   [47:12] She is also working out more advanced techniques to look at the receptors. Dr. David Hill at CHOP is working on similar research. This research has the potential to lead to the development of better tests for EoE.   [47:44] Holly tells Dr. Shreffler this has been such an informative episode with so many tidbits of things to help patients advocate for themselves. Holly thanks him for sharing all of that.   [48:12] Dr. Shreffler is trying to see what can be utilized from their research to make non-invasive tests to identify food allergen triggers for patients so they don't have to go through so many endoscopies. He sees it as a huge unmet need.   [48:31] Ryan thanks Dr. Shreffler for joining us. For our listeners who would like to learn more about eosinophilic disorders, including EoE, please visit APFED.org and check out the links in the show notes.   [48:41] If you're looking to find a specialist who treats eosinophilic disorders, we encourage you to use APFED's Specialist Finder at APFED.org/specialist.   [48:50] If you'd like to connect with others impacted by eosinophilic diseases, please join APFED's online community on the Inspire Network at APFED.org/connections.   [49:00] Ryan thanks Dr. Shreffler for joining us today for this interesting conversation. Holly also thanks APFED's Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron for supporting this episode.   Mentioned in This Episode: Dr. Wayne Shreffler, MD, Ph.D., Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital “Triggers for eosinophilic esophagitis (EoE): The intersection of food allergy and EoE” Dr. Caitlin Burk Dr. David A. Hill   APFED on YouTube, Twitter, Facebook, Pinterest, Instagram Real Talk: Eosinophilic Diseases Podcast apfed.org/specialist apfed.org/connections   Education Partners: This episode of APFED's podcast is brought to you thanks to the support of Bristol Myers Squibb, GSK, Sanofi, and Regeneron.   Tweetables:   “This fascinating problem of food allergy: why does the immune system do that for some people — recognize what should be nutritive and innocuous sources of energy as an immunological trigger? ” — Dr. Wayne Shreffler   “A food allergy; because there is this IgE antibody, we can do skin tests. We can measure that in the blood. It's a useful marker for helping to identify which foods are the trigger.” — Dr. Wayne Shreffler   “EoE is tricky because there's not that clear and easy temporal association between an offending allergen exposure for most people and their symptoms. People don't associate the symptoms with the triggers.” — Dr. Wayne Shreffler   “Everything is shared decision-making. In some cases, it's a shared decision where I have a strong evidence-based opinion. In some cases, there's a lot more room for a range of clinical decisions that could be equally justified.” — Dr. Wayne Shreffler   “Steroids don't help with IgE-related food allergy. They're not effective at blocking that IgE-driven immediate response.” — Dr. Wayne Shreffler   “I'm trying to see what we can utilize from our research to make non-invasive tests to identify food allergen triggers for patients so they don't have to go through so many endoscopies. I think that's a huge unmet need.” — Dr. Wayne Shreffler  

1. Net-zero commitments  One of the central themes of Climate Week NYC 2023 was the widespread commitment to net-zero emissions goals. It demonstrates a growing acknowledgement among businesses: Addressing climate change is a moral imperative and essential for long-term economic resilience. While the tone remained hopeful, it was also realistic—we only have six years left to reduce global emissions by 50% to meet 2030 goals.     2. Investments in renewable energy   Renewable energy took center stage as companies unveiled significant investments in clean energy projects, including massive solar and wind farms. These T&D projects increase the capacity of the grid to move renewable power from the point of generation to the point of consumption, as well as investments in advanced energy storage technologies.   3. Sustainable supply chains  Supply chain sustainability emerged as a critical focus for businesses. Companies announced plans to reduce the carbon footprint of their supply chains by sourcing materials responsibly, optimizing logistics, and adopting circular economy principles. The shift reflects a growing demand from consumers for sustainable products and services and the regulatory landscape.  4. Climate finance and green bonds  Financial institutions and businesses showcased their commitment to climate finance. Green bonds, designed to fund environmentally beneficial projects, gained significant attention. It's a trend that indicates a shift towards sustainable investments, with more capital flowing into projects that combat climate change and support sustainability initiatives.  5. Carbon pricing and emissions reduction  Many businesses pledged to adopt carbon pricing mechanisms within their operations. They also committed to substantial emissions reduction targets, aligning with the Paris Agreement's goals. By putting a price on carbon and actively reducing emissions, these companies are positioning themselves as leaders in transitioning to a low-carbon economy.  6. Technological innovation  Innovations in clean technology were a hot topic at Climate Week. Companies showcased cutting-edge solutions, including carbon capture and utilization, sustainable agriculture techniques, and electric vehicle advancements. These innovations demonstrate that technology is an enabler of sustainability and can drive significant emissions reductions.  7. Climate adaptation and resilience  Climate adaptation and resilience to extreme weather events and rising sea levels were acknowledged as part of the inevitable impacts of climate change. Many announced initiatives to enhance their resilience and support vulnerable communities.  8. Sustainable reporting and transparency  Greater transparency and sustainability reporting were highlighted as essential for accountability. Businesses are committed to disclosing their environmental, social, and governance (ESG) metrics more comprehensively and providing investors and stakeholders with better insights into their sustainability efforts.   Sustain.Life was proud to partner with UN Global Compact USA Network where the message rang clear on the power of data to enable sustainability reporting across the increasingly harmonized global reporting landscape. With recent announcements around CDP's alignment with the ISSB, CSRD, and proposed SEC climate disclosure rules.   ‍

May 5, 2023 Ep 450 - Fighting Cancer with CAR-T Cells Guest: Sarah Roth By Stuart McNish   Cancer – there are more than 200 different types. The odds are high that you or someone you know will get cancer. It is an insidious disease; it can start almost anywhere in your body and spread. Stopping its spread is the work of cancer researchers all over the world and experts in British Columbia are developing breakthroughs.   Recently a multi-site Phase-I clinical trial, launched by BC Cancer and the Ottawa Hospital Research Institute, of made-in-Canada chimeric antigen receptor T-cells demonstrated positive results. CAR-T cells are powerful new tools for treating cancer that are created by genetically modifying a person's existing T-cells. These T-cells are being used to target CD19, a protein marker found on all B-cells in patients with leukemia and lymphoma. Phase-II will allow BC Cancer to produce the CAR-T cell product and run the trial for 20 patients in BC over the next two years. Dr. Brad Nelson, director of Deeley Research Centre, says, “Over the next several years, BC Cancer's CAR-T cell program will expand beyond leukemia and lymphoma to create new and improved treatments for a wide spectrum of cancers.” Sarah Roth, the CEO of the BC Cancer Foundation, says, “The Deeley Research Centre in Victoria is a world pioneer in immunotherapy, harnessing the body's own immune system to prevent, control and eliminate cancer – and has already revolutionized cancer care.” We invited Sarah Roth to join us for a Conversation That Matters about the many research projects underway in British Columbia that will help us defeat cancer. Join me May 16 for Conversations Live - A Vancouver Sun Town Hall: Life Sciences - BC's Innovation Future   https://www.conversationslive.ca/

Wearing a colorful T-shirt with a clever slogan is a wonderful way to share Jesus with others, according to Dinny and Luanne Bullard. These T-shirt evangelists are spreading the good news of the gospel through a Bible-based company called Kerusso. The Bullards travel the country in their 40-foot motor coach and sell Christian apparel and gifts emblazoned with catchy phrases and Bible verses that put a Godly spin on pop culture. For example, one of their most popular glow-in-the-dark Star Wars spin-off shirts reads, “May the Lord be with you!” Dinny says the humorous phrases break down the barriers and help kick-start conversations with strangers about Jesus. To date, Kerusso has printed more than 40 million T-shirts! Grab yours today and lead the lost to Christ.   TAKEAWAYS Kerusso is a Greek word that Jesus used when He told his disciples to preach the gospel to all nations Kerusso has been printing shirts for 35 years and is now the leading Christian T-shirt company in America The average graphic T-shirt has a lifespan of 3,000 views If kids start wearing T-shirts that brag on Jesus, they learn to be unashamed of Christ  

Oliver Newman is joined by The 'Goddess Of Fire' Athena Furie. Athena discusses a range of merchandise designed by Dewinter Designs Uk. These T-shirts and poster items represent the first in Athena's 'Build an Inferno' range where 100% of any profit made from their sale will be donated to charitable causes. Checkout Dewinter Designs Uk on facebook https://www.facebook.com/DewinterDesigns/?tn-str=k*F Athena also discusses her fandom, being a strong role model for girls and her wrestling journey working for Coventry Pro Wrestling, Young Blood Wrestling & Pro Wrestling Subjective. Show your support following https://twitter.com/AthenaFurie and liking https://www.facebook.com/AthenaFireFurie/.

Oliver Newman is joined by The 'Goddess Of Fire' Athena Furie. Athena discusses a range of merchandise designed by Dewinter Designs Uk. These T-shirts and poster items represent the first in Athena's 'Build an Inferno' range where 100% of any profit made from their sale will be donated to charitable causes. Checkout Dewinter Designs Uk on facebook https://www.facebook.com/DewinterDesigns/?tn-str=k*F Athena also discusses her fandom, being a strong role model for girls and her wrestling journey working for Coventry Pro Wrestling, Young Blood Wrestling & Pro Wrestling Subjective. Show your support following https://twitter.com/AthenaFurie and liking https://www.facebook.com/AthenaFireFurie/. --- Send in a voice message: https://anchor.fm/brokenbutglorious/message

Dr. Ted Burns interviews Dr. Stephen Greenberg about his article about the association of inclusion body myositis with T cell large granular lymphocytic leukaemia. Iinclusion body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we prospectively screened 38 patients with inclusion body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD57, and TIA1. Most (22/38; 58%) patients with inclusion body myositis had aberrant populations of large granular lymphocytes in their blood meeting standard diagnostic criteria for T cell large granular lymphocytic leukaemia. These T cell populations were clonal in 20/20 patients and stably present on follow-up testing in 15 patients a median of 350 days later. Cross-sectional data suggested more aggressive disease in patients with such expansions than without. Muscle immunohistochemistry demonstrated invasion of large granular lymphocytes into muscle in 15/15 inclusion body myositis patients but in only 1/28 patients with dermatomyositis or polymyositis. The extent of CD8+ and CD57+ cells in inclusion body myositis muscle correlated with the size of blood large granular lymphocyte populations. Myofibre-invading cells expressed CD57, a marker of persistent T cell exposure to antigen and T cell aggressiveness. Brain. 2016 May;139(Pt 5):1348-60. doi: 10.1093/brain/aww024. Epub 2016 Feb 26.

Dr. Ted Burns interviews Dr. Stephen Greenberg about his article about the association of inclusion body myositis with T cell large granular lymphocytic leukaemia. Iinclusion body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we prospectively screened 38 patients with inclusion body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD57, and TIA1. Most (22/38; 58%) patients with inclusion body myositis had aberrant populations of large granular lymphocytes in their blood meeting standard diagnostic criteria for T cell large granular lymphocytic leukaemia. These T cell populations were clonal in 20/20 patients and stably present on follow-up testing in 15 patients a median of 350 days later. Cross-sectional data suggested more aggressive disease in patients with such expansions than without. Muscle immunohistochemistry demonstrated invasion of large granular lymphocytes into muscle in 15/15 inclusion body myositis patients but in only 1/28 patients with dermatomyositis or polymyositis. The extent of CD8+ and CD57+ cells in inclusion body myositis muscle correlated with the size of blood large granular lymphocyte populations. Myofibre-invading cells expressed CD57, a marker of persistent T cell exposure to antigen and T cell aggressiveness. Brain. 2016 May;139(Pt 5):1348-60. doi: 10.1093/brain/aww024. Epub 2016 Feb 26.

Herpes simplex virus type 1 (HSV-1) is a double-stranded DNA virus that infects humans and, after a primary lytic infection, establishes lifelong latency in the sensory neurons of the trigeminal ganglia (TG). HSV 1 latency is accompanied by a chronic immune cell infiltration of the TG, the infiltrate being mainly composed of CD8+ T cells. These T cells are believed to control viral latency, but cellular and viral factors like viral microRNAs are also considered to play a crucial role in the establishment and maintenance of viral latency. In the present work, it was investigated whether the tissue-infiltrating T cells are clonally expanded, which would indicate that these T cells are activated by antigen. By applying complementarity determining region 3 (CDR3) spectratyping and immunohistochemistry, several clonal expansions were identified in the TG-resident T cells. In addition, several T cells were present that seemed to be unspecific bystander T cells. Strikingly, some expanded T cell clones were present in the right and left TG of the same individual. This strongly suggests that similar antigens are present in both TG and that the infiltration of immune cells to the TG is driven by antigen. The morphology of the TG was investigated by immunohistochemistry and in situ hybridiza¬tion. Analysis of the distribution of T cells throughout the TG provided puzzling results: unexpectedly, most neurons surrounded by T cells did not harbour the only known prominent transcript during latency, the latency associated transcript (LAT). Whether these neurons do actually harbour latent virus was addressed by a combination of LAT in situ hybridisation, T cell immunohistochemistry, and single cell analysis of laser microdissected sensory neurons by PCR. This analysis revealed that only LAT+ neurons were harbouring HSV 1 DNA and viral microRNAs. Also, mRNA for a viral gene product was only detected in LAT+ neurons. All analysed LAT– neurons were devoid of viral microRNAs and DNA of HSV 1. DNA of HSV 2 or varicella-zoster virus (VZV) was not detected in any of the excised neurons. Alto¬gether this indicates that in the vast majority of infected human neurons, HSV 1 latency is not directly controlled by T cells, but rather by cellular or viral factors like the miRNAs. Our data suggest that CD8+ T cells only come into action if these mechanisms are overrun.

Interactions between regulatory T lymphocytes and other cells are assumed to occur at the level of the cell surface. T cells which suppress the generation of specifically effector cells have been described as having antigenic, idiotypic, allotypic and I-region specificity1−4. Other T suppressor cells generated by in vitro cultivation with or without mitogenic stimulation5,6 have suppressive activity for T and B cells but no specificity can be assigned to them. These T suppressor cells (Ts) inhibit various lymphoid functions—this either reflects their polyclonal origin or indicates that the structures recognized by the Ts receptors must be common for many cell types. Carbohydrates on cell membrane-inserted glycoproteins or glycolipids might function as specific ligands for recognition by cellular receptors or soluble factors. Almost all cell-surface proteins of mammalian cells are glycosylated. There is evidence for lectin-like carbohydrate binding proteins not only in plants7 but also in toxins8, viruses9, prokaryotic cells10 and even mammalian cells, including T cells11. A functional role for these lectin-like proteins has been described for slime moulds and suggested for the selective association of embryonic cells12,13. We report here that addition of a monosaccharide can counteract the effect of T suppressor cells during the generation of alloreactive cytotoxic T cells (CTLs) in vitro.