Personalised Drugs

Hello beautiful people, I hope you are all doing well. I know its been a long time since I put anything up on this page, turns out second year at vet school is quite tricky and overwhelming so I've been taking each day as it comes and trying not to get too stressed, at the end of the day my mental health will always come first. I hope you are having a lovely week and I just thought I'd pop on here to talk about some things we've learnt in lectures recently which I found super interesting as I did do a post on this topic a while ago called designer drugs I believe. So here goes I'm going to explain the basics behind the drugs and hopefully some of you will be able to follow along.

So T-cells make up a big part of our immune system. At school you may have been taught about T-killer cells which we call CD8+ t-cells and then you get T-helper cells which we call CD4+. this CD business is basically a protein on the T-cells that helps to determine its character and what cells it binds to. The cells T-cells bind to have MHC proteins on them which stands for Major Histocompatibility Complex. There are two classes of these MHCI and MHCII, it is these that the t-cell receptor site recognises during an immune reaction. CD8+ binds with MHCI which is found on any nucleated cell and CD4+ binds with MHCII which is found on antigen presenting cells (note that these can also be nucleated cells).
The genes to make MHC are linked and very complex on one specific chromosome in DNA. The location differs between species. These genes also encode for antigen presentation and processing.  Some of the reasons MCH are so good is because they’re polygenic and contain several different copies of MHCI and MHCII, they’re also polymorphic so many alleles of each gene in the population so greater combinations. Each individual express diff number of MHC antigens, the specific set of MHC expressed is called “tissue type” this is used when finding matches for organ transplantation. When looking at the genetics of MHC, a haplotype is taken from each mother and father and this makes a new combination, these combinations are much like the mendelian cross squares. This makes it very rare to have a tissue type match which is why graft rejection is still such a major issue. 
Only mature t-cells express a t-cell receptor with the CD 4 or 8 protein. The recognition of peptide-MHC involves both co-receptors, the TCR and CD bind to different sites on the MHC molecule so 1 MHC to both receptors, the TCR has pMHC recognition and CD4/8 enhances sensitivity. This binding isn’t dependent on a peptide being present as CD8/4 will bind without it and hence accelerate the TCR interaction with the peptide, the joining of CD8 isn’t enough to activate the t-cells are overcome the activation threshold just lower it, as MHCI doesn’t have a high enough affinity to the CD8. Once a T-cell has bound the two receptors onto the MHC then signals start to cascade which causes cytokines to be released which effectively kill the harmful pathogen in the body. 

The different type of T-helper cells. TH1 activates macrophages to kill intracell organisms and stimulated CD8 t-cells. TH2, helps B-cells differentiate to plasma cells to secrete Ab’s (antibodies). TH17 recruits’ neutrophils to infection sites. Remember CD4 are T-helper cells. The immune response can be polarized towards Th1 or Th2 which is called immune deviation. Each are mutually antagonistic and depend on the CD4 which is triggered. Th1 cells produce IFN (interferon) gamma which inhibits Th2 (cytotoxic cell mediated immunity. Th2 cells make IL-4 and IL-13 which inhibit Th1 cells this is humoral immunity (soluble antibody immunity). Incorrect deviation is thought to contribute to pathology e.g. a dog with leishmaniosis requires a strong Th1 polarization in order to control this protozoal infection. Failure leads to chronic multisystemic disease and death. 

All CD4 t-cells arise from common precursor, the wat antigen interacts with APCs determines cytokine prod by APCs. It is a variation of 3 signals that causes different effector functions of CD4 t-cells. 

Okay so there is some of the science, now I'm going to try and explain.When presented with an antigen initially you get natural antigens then you get in day 2-7 the T-independent antibody and finally 5-12 day you get the T-dependent antibody, this is the adaptive immune response and is slower to get going. As antigen conc decrease and the immune response matures and there is more of a selection for high affinity BCR (b-cell receptor) compared to low affinity BCRs. So only responses with high affinity BCRs have a response that persists.  

Monoclonal antibodies can be used for allergy test, therapeutic monoclonals like the treatment of cancer or blocking a viral infection. Monoclonal antibodies are made by injecting a mouse with an antigen, the mouse responds to numerous determinants and activates B-cells of the different epitopes. The spleen is then removed from the mouse, which contains some antigen-specific B-cells and not antigen-specific. They then get the myeloma (plasma cell) cell line ‘immortal’ as neoplastic so they will grow continuously in cell culture.  Then the spleen B-cells are mixed with the myeloma cells, PEG is added which causes cell fusion and the fusion allows the exchange of nuclear material to create immortal plasma cells that produce antibodies these cells are called hybridomas. HAT is then added which unfuses B-cells and they die along with any unbound myeloma cells. These are dilutes into single cell pots, then cloning happens and you get pots of monoclonal cells, these can be harvested but they’re mouse antibodies so have to be humanized or caninized.
There is also Adoptive T-cell therapy, which is a treatment used to help the immune system combat diseases like cancer and infections via viruses. T-cells are collected from a patient and grown in the lab. this increases the number of T-cells that are able to kill cancer cells or fight infections. there T-cells are given back to the patient to help the immune system fight disease. It is also called tumour infiltrating lymphocyte therapy, when injected into the tumour the t-cells help the body attack the diseased cells and has been described to 'melt' the tumour.

There is also a chance to develop T-cells that express cancer specific TCRs, which seems amazing, being able to produce a large amount of CD8 t-cells in a very short amount of time and increase the affinity of the TCR to the cancer cells, however in reality it is very tricky to identify a suitable MHCI restricted tumour rejection antigen, and to isolate tumour specific TCR.

There has been a huge breakthrough in checkpoint inhibitors. the T-cells within the immunosuppressive tumour microenvironment express many Co-inhibitory receptors these deliver a negative signal to the t-cells which prevents them from activating and destroying cancer cells, so monoclonal antibodies that block the inhibitory receptors have been developed and are being used to treat humans with metastatic melanomas. 

I hope you enjoyed that and you managed to follow along at least just a little bit. I am slowly getting into the swing of university and sports, I've decided to swim 2 times a week and gym 5 times a week plus sometimes trying to incorporate some gym classes. It's all a work in progress at the beginning of university this term I did really struggle with my mental health but I'm now focussing on the small positives each day. I hope you all continue to have an amazing week and just remember to smile because you never know it could make someone's day. I will post when I next feel like it, see you then!