The Importance of Correctly Diagnosing Immunocompromised Individuals and the Role of T Cells in Diagnostics
Rimini, 28th February 2022 – How does our immune system react to pathogen invasions and what is the importance of the cell-mediated response to diseases that are also extremely diverse, such as tuberculosis and COVID? These are the topics of the workshop promoted today by Oxford Immunotec, leader in the production and marketing of diagnostic tests based on T cells and now part of PerkinElmer Inc., on the XLIX National Congress of the AMCLI (Association of Italian Clinical Microbiologists) in Rimini. The event will provide an opportunity for discussion not only to provide an up-to-date overview of technological innovation in diagnostics, but also to clarify the role of specific cell populations such as T lymphocytes (or T cells), which are responsible for immunological memory.
The human immune system boasts a much higher level of complexity than other animal species, as it has several cell populations (T and B lymphocytes, macrophages, presenter cells, NK cells, etc.) and molecules (antibodies, cytokines and complement) that can respond in a coordinated manner to the entry of a foreign agent. Refined mechanisms, however, are very efficient when they work well, but can create problems, even serious ones, if one or more steps are altered. As Dr Oscar Matteo Gagliardi, University of Milan – School of Pharmacology and Clinical Toxicology, explains: “When we talk about the immune system, we must imagine a homeostatic balance, i.e. a complex system integrated between several functions: on the one hand the innate response, the acquired response and the physical barriers that resist pathogen invasion. When something disrupts this homeostatic balance – think of a very heterogeneous group of pathologies – immunocompromise occurs, i.e. an increased susceptibility to infection”.
T cells are an acquired component of the immune system, orchestrating all immune activity through the production of substances such as interferon-gamma and interleukin-2. They are so called because they mature in the thymus and circulate in the blood and lymphatic system, recognising the body’s cells as their own, thus preventing them from being attacked. T lymphocytes are activated, however, when receptors on their surface recognise antigens (foreign agents) specific to that receptor, with substantial differences between naïve T cells, which take on average two days to respond to the antigen because they have never encountered it, and memory T cells, which react to the antigen in just two hours and lead to enhanced responses upon repeated exposure to the same antigen. T cells activate a pool of cells to boost the immune response, 95% of which die at the end of the process. The remaining 5%, however, constitute the memory compartment.
The role of T cells in diagnostics is fundamental, as it enables the analysis of various compounds such as cytokines, molecules expressed by the cells, which are now increasingly in the limelight for their involvement in SARS-CoV-2. Dr Gagliardi explains: “We must remember that SARS-CoV-2 is genetically like SARS-CoV-1, sharing 79.5% of the genetic sequences, which justifies both the similarities and the differences. Even before the current pandemic, SARS-COV-1 studies were conducted to investigate the immune responses of individuals who had contracted this virus. The fact that most individuals who contracted SARS-CoV-1 demonstrated a relevant T response in the face of a null antibody and B response may suggest that the T response in SARS-CoV-2 may also be maintained over time. In the case of SARS-CoV-1, in fact, antibodies and the B response are present after infection but last only 4 years, whereas the T response persists even after 11-17 years. Most of the current studies on SARS-CoV-2 are based on serological assays, i.e. evaluating serological trends over time, but the T response may be a complementary investigation to the antibody level and may in the future become a parameter of protection in vaccinated individuals with undetectable antibody levels. We already know how the Omicron variant ‘evades’ the vaccine antibody response, although severe disease is nevertheless prevented in the vaccinated due to almost unchanged protection by the vaccine-induced T response”.
In its evolution, the T cell differentiates with a different pattern of cytokine functions that it will secrete and different locations where it will lodge. Dr Oscar Matteo Gagliardi explains: “We have evidence of several memory T cells that are also present at organ level, for example in tuberculosis (TB) we have a T response that is resident in the lungs, so that when the microorganism arrives there is already a T response. The potential of these cells is immense, with possible developments also in pharmacology. An innovative approach against viruses involves focusing on the cells of the immune system and not on a drug”.
T cell diagnostics is also an effective identification tool that influences the therapeutic strategy to be implemented. As in the case of cytomegalovirus (CMV) infection which, even in Italy, is endemic in about 83% of the general population and up to 86% of the female population. And yet, although this infection is asymptomatic in immunocompetent subjects, i.e. in healthy people, for immunocompromised subjects, such as transplant patients who experience a kind of ‘controlled immunosuppression’, CMV becomes one of the most common infectious complications, as well as a cause of increased morbidity and mortality. “In this case, therapeutic strategies require the use of antiviral drugs,” comments Dr. Gagliardi, “but to avoid their indiscriminate use on all transplanted subjects, thanks to specific tests such as circulating DNaemia, which allows us to understand when there is reactivation, we can define which patients actually need them. This reduces the risk of adverse effects linked to the use of antiviral drugs used in CMV therapy, such as myelosuppression, which paradoxically exposes transplanted patients to a greater risk of infection”.
By identifying whether the transplant recipient has a high T response, i.e. has adequate protection against contracting cytomegalovirus, serological testing over time and the administration of the antiviral drug are avoided.
THE CELL-MEDIATED RESPONSE IN TUBERCULOSIS
Tuberculosis (Tb) is an infectious and contagious disease caused by a bacterium, Mycobacterium tuberculosis, commonly called Koch’s bacillus, which mostly affects the lungs but can also affect other parts of the body, including the urinary tract, central nervous system, bones, joints and other organs. If left untreated, the disease can lead to death, and is still one of the ten leading causes of death worldwide. Not everyone who becomes infected develops the disease; the immune system can cope with the infection and the bacterium can remain dormant for years. This condition is called latent tuberculous infection and about a quarter of the world’s population is affected. People with latent TB infection have no symptoms and are not contagious. Many people will never develop the disease, while others may become ill after years. It is estimated that 5-15% of people with latent infection develop the disease during their lifetime. People at high risk of developing active TB disease are also those with other conditions that weaken the immune system.
Although the immune mechanisms of TB are not yet fully understood, we know that the immune system blocks the virus within a granuloma after infection, making it almost impossible to detect. Today, interferon-gamma release assays (IGRA) can measure the immune system’s response to an antigen derived from the mycobacterium tuberculosis. Thanks to technological innovation, Oxford Immunotec’s T-SPOT.TB tests are the only IGRA available using simplified ELISPOT (enzyme-linked immunospot) technology: these tests are extremely sensitive as the target cytokine is captured directly by the secreting cell, before it is diluted in the supernatant, captured by receptors in adjacent cells or degraded.
“T cell diagnostics could be applied soon to all diseases in which these cells play a role,” Dr Gagliardi concludes, “starting with autoimmune diseases such as diabetes, celiac disease and lupus. We are going to evaluate the cellular response and how to intervene, as we have started to do in oncology with CAR-T, developing innovative personalised therapies that desensitise T cells”.