How can we erase immunological memory or "devaccinate" people?
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jnikolaAug 25, 2022
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The point is to think of a way of resetting the immune system memory, either by clearing the antibodies, resetting the memory T-cells or by other means.
Why?
If we could find a way how to devacccinate people, we could also find a way how to effectively fight autoimmune diseases and allergies. In some cases where secondary exposure to the same antigen is much more ineffectivethan the primary (HIV, dengue fever), we could find a way to reverse it and make patients respond better the second time they are exposed.
How to contribute?
new way of ereasing the memory of immune system
a method of removal of specific antigens from the organism (along with resting lymphocytes)
any example of how number of antibodies, epitopes or other immuno memory is depleted
new knowledge that can help us find a way to reset the immunological memory
Background
When we refer to immune memory, we actually think of an adaptive immune response mediated by memory lymphocytes (T and B cells). This type of immune response is provoked by vaccination or after a primary immune response against the antigen and is considered to be beneficial for the patient. However, the adaptive immune response can be detrimental to the patient. Some of the examples are hayfever, asthma, other autoimmune diseases or allergies.
The concept works like this (in short). B cells recognize the antigen, produce the antibodies and present MHC I complex to effector T cells. They activate, proliferate and act pro-inflammatory. After a while, most of the effector T cells degrade, but antibodies and a small number of resting T and B cells remain in the body and can be activated upon reinfection. Next exposure results in faster and more specific response, clearing the pathogen more effectively.
Examples
An example of how immune memory can be depleted is the measles infection in unvaccinated children, which completely removes the immune memory to other pathogens. Researchers detected substantial reductions in the number of pathogen epitopes recognized after measles, but limited changes in the absence of measles. If children were previously vaccinated with MMR vaccine, no loss of antibody count and diversity was reported. However, infecting people with measles seems like a wrong way of doing the right thing! Also, more proof-of-concept and application experiments are needed.
Some lessons from Measles induced ‘Immune Amnesia’
Subash ChapagainAug 25, 2022
Thank you for posting this topic. This is a very interesting issue and a million-dollar question. I, too, have pondered upon this topic quite heavily recently. As a virologist in training, I tried to gather some information about 'immune memory depletion', which I believe will be useful for this session:
Immune memory and the Measles
Measles infection causes severe immune suppression and amnesia, and the direct infection of lymphocytes could be one of the reasons behind it. Still, this was not known to be the definitive norm. This possibility was dismissed based on two major observations during measles infection, a) lymphocyte counts rapidly return to normal after the clearance of the virus, and b) during the peak viremia, only 1-5% of total lymphocytes in the peripheral blood is infected .
In 2012, another seminal animal study investigated the aetiology of measles and measles-related immune suppression. Standing on the supportive foundation established in the previous animal study that showed MeV infection of a high percentage of lymphoid tissues and biased memory T cells. Rhesus macaques were used again in this experiment . In this study, the observations from earlier experiment were corroborated. Lymphoid tissues reveal predominant measles infection even at macroscopic investigation, and the high percentages of B-lymphocytes and CD45RA memory T Cells were infected. In tonsils, peyer’s patches , tracheobronchial lymph nodes and PBMCs, it was seen that memory T cells as compared to naïve T cells were significantly selectively infected. This distinction was not visible for B-cells.
Based on the observations gathered from earlier in vitro and the in vivo experiments, the researchers proposed a measles infection model that is compatible to the ‘measles paradox’. Measles paradox is the phenomenon where individuals retain a strong immunological defense against the measles virus after viral clearance, whereas all other immunological memory against other pathogens is apparently lost. This leads to the condition of measles-induced immune amnesia.
The model suggests that after the measles infection associated viremia, a serious depletion of memory T cells and B cells occurs. After the second week of infection, the lymphocyte population looks as if it is returning to normal just because the number of MV-specific and bystander T and B cells is restored, whereas the number of memory T cells continues to be suppressed for at least six weeks. In this manner, by infecting and eliminating the preexisting memory cells that express high levels of CD150, Measles erases the recollection of past exposures to microbes and ‘resets’ the host’s defence system back to its default.
The findings from the above-mentioned animal models were corroborated by the observations from a large-scale human epidemiological study conducted in the Netherlands after a Measles outbreak in 2013. The study was published in Nature .
Molecular and genetic basis for B-cell repertoire depletion
Next, in 2019, a group of scientists sought to investigate the actual genetic mechanism that might be related to immune amnesia after measles infection. In this study, the group used B cell receptor sequencing to see what changes in the gene were behind the speculated suppression of antibody repertoires against other pathogens after a measles infection. When the cells were sequenced for the B cell receptor Variable region (V-J) gene termed complementarity determining region (CDR3), they found that this region was considerably shortened after measles infection. The V-J gene frequency had a much lower correlation post-infection as compared to pre-infection. This led to an incomplete reconstitution of the naïve B cell pool and compromised the immune capacity to previously encountered pathogens. Moreover, surrogate ferret models of measles infection were also used to demonstrate that the depletion of vaccine-acquired immunity to the influenza virus led to a compromised recall response and increased severity of non-measles diseases .
With this information so far, what can we do next?
Can we edit the naive B cells selectively?
Can we 'engineer' the Measles virus optimally to induce required immune amnesia without the associated pathology?
Subash Chapagain thank you for the detailed comment and the knowledge you shared with us. I am glad we have a great virologist here to discuss the topic with.
The last question you wrote is the one that got me thinking the most. Obviously Measles virus induces immune amnesia. I'll try to look for papers that may be discussed different types of measles virus parts being used for the infection and the corresponding response. That could be a nice way to see which structural part or mechanism of the viral infection is responsible for the specific paradox you mentioned. Have you heard of something similar?
Once again, great contribution!
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Consider the role of 'invariant T cells'
Subash ChapagainAug 26, 2022
Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that are present in humans and distributed throughout the blood and mucosal sites. MAIT cells are different than the regular T cells in that they do not express the regular T cell receptor but rather express the semi-invariant TCR-alpha chain. Another feature that makes MAIT cells distinct is that they are restricted not by Major Histocompatibility Complex (MHC), but by MHC-related protein 1, MR1. While the conventional T cells remain naïve until antigenic stimulation in the periphery, MAIT cells are activated and have full effector capacity before exiting the thymus. MAIT cells are thought to have evolved to defend against bacteria and secrete pro-inflammatory cytokines and cytotoxic molecules in response to microbial infections .
MAIT cells exit the thymus with full functional capacities and they move to mucosal tissues via blood. When an antigen presenting cell presents MAIT with an antigen, the cells can enter three tentative fates: a) TNF-IFN-gamma mediated activation for direct intracellular infection responses, b) production of perforin and granzyme B for lysis of the infected cell, or c) clonal expansion to form a pool of memory cells. However, the third option is yet to be fully confirmed .
MAIT cells express SLAM, and due to this, they are permissible to MeV. Once infected by the measles virus, these cells are no longer able to execute their effector pro-inflammatory as well as helper functions, and it leads to a compromised immunity against bacterial pathogens. Hence, MAIT cells infection by Measles leads into immune suppression and possibly immune amnesia.
Though this is tightly linked to measles-induced immune amnesia, one possible approach would be to investigate if we can selectively 'silence' the effector function of MAIT cells by mechanisms other than measles infection.
Resetting "immunological memory" via conditioning immunochemotherapy
jnikolaDec 07, 2022
Erasing "immunological memory" by treatment of hematopoietic stem cells with a conditioning immunochemotherapy.
In short: Extract immune cells - filter and reset - put back in - production of antibodies de novo
Background
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system in which patients experience progressive neuronal damage due to inflammation, demyelination, glial activation and abrupted metabolism. Adaptive immune cells (T and B cells; especially CD4+ T cells - TH1, TH1*, TH17 and Tregs) are activated in the periphery and invade the brain where they induce inflammation. In other words, normally-present brain proteins such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP) and others trigger an immune response from CD+ T cells. Current treatment strategies include drugs like anti-CD20, anti-CD52, anti-VLA4, and cladribine which reduce the annual relapse rate by up to 70%. If the disease is reoccurring, the patients are submitted to the most successful therapy - autologous hematopoietic stem cell transplantation.
Autologous hematopoietic stem cell transplantation (aHSCT) is consisted of extracting patients hematopoietic stem cells (HSC; cells which produce blood cells which later are involved in immunity), conditioning them with high-dose immunochemotherapy and reestablishment of a new immune system from reinfused "resetted" autologous hematopoietic stem and progenitor cells (HSPC) (Figure 1). Besides MS, aHSCT is used to treat Hodgkin lymphoma (HL) or chronic myelogenous (myeloid, myelocytic, granulocytic) leukemias.
Figure 1. aHSCT procedure. Pathogenic T cells present in the patient. 1) Mobilization of HSCs from bone marrow by injection of cyclophosphamide intravenously and granulocyte-colony stimulating factor (G-CSF) subcutaneously. 2) Collection of patient blood cells (CD34+ or all) by leukoapharesis. 3) Deleting the "immunological memory" by treatment of extracted blood cells with a combination of cytotoxic drugs. 4) Reinfusion of ablated blood cells (transplantation) along with antithymocyte globulin to deplete T cells. 5) New CD8+ and CD4+ T cells produced by the "new thymus" through infection and reimmunization. No pathogenic T cells present. Taken from Muraro et al .
Cytotoxic drugs used in aHSCT
In aHSCT, high doses of busulfan and cyclophosphamide, cyclophosphamide and anti-thymocyte globulin (ATG) were previously used, but stalled due to serious adverse effects and high disease reoccurence. In Europe, the most used therapy is BEAM (or BeEAM) consisting of bis-chloroethylnitrosourea (BCNU) or bendamustine, etoposide, cytosine arabinoside (ARA-C), and melphalan.
Ideas
Use cytotoxic drugs to filter out immune cells with a specific immune memory - solution to this challenge!
Remove immune cells which are the result of vaccination
Create a repertoire of T and B cells needed for a functional immune system to work properly
Fun fact - when the COVID-19 vaccination started, several methods on how you can devaccinate yourself appeared. The methods included cupping, a Chinese traditional practice to promote healing by drawing fluid towards the treated area and improve the flow of energy. The other method used snake venom to extract the vaccine minutes after it's received (manual shown in Figure 1).
jnikola Aug 25, 2022
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