Assignment 1: Find me a -mAb drug assignment

Monoclonal antibodies (mAbs) are a type of targeted drug therapy that can recognize specific proteins; these drugs stimulate the immune system. Specific mAbs, are beneficial for treating cancers and other life-threatening diseases. One monoclonal antibody drug in particular, alemtuzumab, is useful in treating multiple sclerosis (MS), a disabling disease of the central nervous system (1). MS comes from an unknown origin and can be defined as an immune-mediated disease that causes the body’s immune system to destroy the mylen surrounding the nerve fibers in the brain and spinal cord (8). Although alemtuzumab primarily aims to treat lymphocytic leukemia, it is recommended for MS when other treatments have proven ineffective. Alemtuzumab was manufactured in the Department of Pathology in Cambridge, United Kingdom during the 1980s, hence the brand name Campath-1H.  This drug was the first monoclonal antibody to be humanized and used in therapy (5). The treatment schedule of alemtuzumab is desirable to its patients because of its easy administration, however, limited patients within a specific disease window have an opportunity to use this treatment method because of its safety profile (4). Lemtrada (alemtuzumab) is a disease-modifying drug that is administered as an intravenous infusion (drip) in two treatment courses that are twelve months apart; the approved treatment dose is ​​60 mg over 5 days for the initial course and 36 mg over 3 days for subsequent courses (3). Lemtrada is a trademark of Genzyme, a Sanofi Company, and was FDA approved in 2014. This method reduced the number of MS relapses by seventy percent. Serious side effects of this treatment include thyroid disorders, kidney problems, increased risk of infection, and blood clotting problems (2). 

Sketch of Alemtuzumab

Alemtuzumab targets and binds to CD52, a glycoprotein prevalent in lymphocytes ( T and B cells), monocytes, and eosinophils (7). This mAb is a genetically engineered human immunoglobulin subclass gamma 1 (IgG1)  kappa monoclonal antibody. It contains six complementarity-determining regions that originated from an IgG2 rat monoclonal antibody, which is specific for CD52 (6). In the average immune response, the function of regulatory T-cells is to suppress autoreactive T-cell proliferation through the production of cytokines and contacting effector T-cells. Patients with MS have impaired suppressive function. The primary job of alemtuzumab is to deplete the circulating T and B cells using antibody-dependent cytolysis and complement-dependent cytolysis. The depletion of T and B cells is followed by lymphocyte repopulation. Both B and T cell populations should return to normal before the twelve-month mark of treatment (3).

References

1. Berger, T., Elovaara, I., Fredrikson, S. et al. Alemtuzumab Use in Clinical Practice: Recommendations from European Multiple Sclerosis Experts. CNS Drugs 31, 33–50 (2017). https://doi.org/10.1007/s40263-016-0394-8
2. “FDA Approves Lemtrada™ (Alemtuzumab) for Relapsing MS – Update.” National Multiple Sclerosis Society, https://www.nationalmssociety.org/About-the-Society/News/FDA-Approves-Lemtrada%E2%84%A2-(alemtuzumab)-for-Relapsing. 
3. Havrdova E, Horakova D, Kovarova I. Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use. Ther Adv Neurol Disord. 2015 Jan;8(1):31-45. doi: 10.1177/1756285614563522. PMID: 25584072; PMCID: PMC4286943.
4. Jennifer R. Evan, Subutay B. Bozkurt, Nikita C. Thomas & Francesca Bagnato (2018) Alemtuzumab for the treatment of multiple sclerosis, Expert Opinion on Biological Therapy, 18:3, 323-334, DOI: 10.1080/14712598.2018.1425388
5. Katsavos S, Coles A. Alemtuzumab as Treatment for Multiple Sclerosis. Cold Spring Harb Perspect Med. 2018 Oct 1;8(10):a032029. doi: 10.1101/cshperspect.a032029. PMID: 29500306; PMCID: PMC6169984.
6. Li Z, Richards S, Surks HK, Jacobs A, Panzara MA. Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis. Clin Exp Immunol. 2018 Dec;194(3):295-314. doi: 10.1111/cei.13208. Epub 2018 Oct 1. PMID: 30144037; PMCID: PMC6231011.
7. Matthews, P.M. Chronic inflammation in multiple sclerosis — seeing what was always there. Nat Rev Neurol 15, 582–593 (2019). https://doi.org/10.1038/s41582-019-0240-y
8. “Multiple Sclerosis.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 24 Dec. 2022, https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269.

Assignment 2: Scientific Literary Analysis

Innate immunity modulates autoimmunity: type 1 interferon-b treatment in multiple sclerosis promotes growth and function of regulatory invariant natural killer T cells through dendritic cell maturation

Hypothesis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that affects millions of people. Since MS is mediated by T-cells, Type 1 interferon-b (T1IFN-b) therapy has proven effective in reducing the number of patients battling recurring illnesses. However, the mechanisms behind its success still remain obscure. The confusion stems from an innate cytokine’s ability to counter-regulate T-cell autoimmunity in patients with MS when its primary function is to enhance T-cell regulation.  Recent data indicates that innate cytokines have the potential to affect nearly every cell type and immune function, and can exert multiple actions on innate and adaptive immune responses; more specifically, T1IFNs are able to mold the responses of natural killer cells (NK cells) and CD8+ cells, increase the secretion of cytokines and growth factors for T cells and regulate dendritic cell (DC) maturation and function (1). Based on this information it can be postulated that since T1IFN-b promotes regulatory mechanisms, then it is capable of preventing autoimmunity. Hypothetically, T1IFN-b would enhance the function of invariant NK T cells (iNKT cells), which are responsible for preventing autoimmune diseases.

Aims

The intention of this experiment was to determine if T1IFN-b has an effect on iNKT cells by promoting activation and their regulatory functions. The cytokine secretions and percentages were measured from patients diagnosed with MS that were using T1IFN-b as treatment. The materials and methods used to collect, analyze, and compare the data were adequate. The first method consisted of monoclonal antibodies and phenotypic analysis, excluding dead cells from all experiments. Next, there was DC derivation from peripheral blood monocytes and culture. Followed by iNKT cell cultures and proliferation assay, cytokine assays,  and the statistical analysis of the number of iNKT cells in untreated individuals versus the number of cells in T1IFN-b treated patients using a non-parametric Mann-Whitney test. Subjects used were of different ages, disease stages, and severity; however, none relapsed after 2 years of therapy. Table 1 includes information and a comparison of the MS patients (1).

Results

The percentages of iNKT cells in peripheral blood mononuclear cells (PBMC) were measured before and after T1IFN-b treatment. Data shows there was an increase in iNKT cells in the PMBC in T1IFN-b treated patients versus their samples collected before treatment. Treatment also proved to promote the function of regulatory iNKT cells but did not directly affect cell growth or function. This was contributed to the fact that iNKT cells act more as T lymphocytes when interacting with T1IFN-b. T1IFN-b  also had an influence on dendritic cells by improving their antigen-presenting capacity both in vitro and in vivo. T1IFN-b greatly increased the cell quantity of iNKT cells and improved NKT cell cytokine release. The results of this study suggest that T1IFN-b enhances the innate immunity that conditions myeloid dendritic cells that result in the expansion and function of iNKT cells, therefore supporting the hypothesis (1). 

Discussion/Summary

Innate cytokines aid in fighting infections by modulating NK cells and myeloid DCs. The data from this experiment confirms that T1IFN-b treatment does induce selective DC maturation and increases the expression of NKT cells. iNKT cells, innate lymphocytes, and in inhibiting T-cell immunity and building tolerance to autoimmune diseases. T1IFN-b enhances DC’s ability to activate iNKT cells. In treated patients, T1IFN-b would modulate immature DCs where they would present antigens to iNKT cells. This results in the expansion/activation of iNKT cells and a higher response to antigenic stimulation. The data concludes that T1IFN-b treatment pre-activated iNKT cells, giving them the ability to respond efficiently to antigen stimulation and T-cell responses. Data also supports the promoted cell growth and function of regulatory iNKT cells and explains how T1IFN-b is effective against MS (1). This information presented relates to course materials because it illustrates how NK and T cells are applicable in real-world situations and how important it is to understand their mechanisms in order to help treat serious illnesses.

Works Cited

1. Gigli G, Caielli S, Cutuli D, Falcone M. Innate immunity modulates autoimmunity: type 1 interferon-beta treatment in multiple sclerosis promotes growth and function of regulatory invariant natural killer T cells through dendritic cell maturation. Immunology. 2007 Nov;122(3):409-17. doi: 10.1111/j.1365-2567.2007.02655.x. Epub 2007 Jul 6. PMID: 17617156; PMCID: PMC2266024.

Assignment 3: T cells and COVID vaccine summary

Severe acute respiratory syndrome coronavirus (2 SARS-CoV-2), more commonly known as COVID-19,  is thought to have originated through zoonotic transmission from a seafood market in China. As the disease quickly ran rampant, it was realized that human-to-human transmission played a large role in the COVID-19 pandemic.  The virus collected a large death toll and forced many countries into lockdowns to maintain social distancing because of its infection rate(1). The highly contagious virus with fatal outcomes increased the demand for a vaccine. The production of a vaccine was essential for normality to return amidst the pandemic. However, in order to produce a vaccine one would have to understand the mechanics behind COVID-19’s attack on the immune system. 

The production of COVID-19 vaccines happened in a very short period of time, and there are still many unknowns on how the vaccines aid the immune system against the virus. Many studies have primarily focused on the concepts of humoral immunity using neutralizing antibodies (NAb) responses. This study emphasizes the data supporting the large role cellular immunity has by using T-cell responses to fight the virus and recognize viral variants that were not detected by NAb responses. While antibodies, such as IgG, can prevent an infection in high concentrations, memory T cells are able to provide another layer of protection. Unlike antibodies, T cells cannot prevent the acquisition of the virus, however, once the host cell is infected, T cells are quickly able to limit the spread and replication of the virus (2). Although T cells would not stop the infection from occurring, they are beneficial in preventing the disease from further spread to other parts of the body by eliminating infected host cells. The figure presented in the study demonstrates how different the mechanisms of humoral and cellular immunity are in preventing infection, but also how they complement each other to effectively eradicate COVID-19 (2).

Cellular immunity has proven to be more effective than vaccines utilizing  NAb responses. Newer variants of the COVID-19 virus are highly transmissible and can easily escape NAb receptors, deeming vaccines equipped with this method ineffective. As learned in class, the immune system depends on memory cells to prevent reinfection. When a booster vaccine is administered, it is converted into plasma cells in order to make new antibodies. The memory B and T cells created both protect from disease. T cells utilize different mechanisms to prevent the spread. CD8+ T cells directly kill cells that are infected while producing antiviral cytokines and inflammatory molecules, CD4+ helps support B cell responses or acts similarly to CD8+ cells. These types of cells can be maintained for decades making them crucial for the use of vaccines. Another benefit to T cells is that they are not limited to the same domains as NAbs. The chance of escape increases when basing a vaccine on antibodies alone because of their receptor recognition (2). 

Studies have shown that there was a direct correlation between vaccine failures and a lack of COVID-19-specific CD8+ cells. This suggests that while humoral immunity does prevent the acquisition of the virus, cellular immunity is vital in preventing the infection from recurring and spreading within the body. T cells protect against the viral variants that are increasingly escaping NAbs and prevent severe infection. This article efficiently argued that T-cell immunity against COVID-19 should be considered when improving the vaccines that are currently available.

Works Cited

1. Koichi Yuki, Miho Fujiogi, Sophia Koutsogiannaki, COVID-19 pathophysiology: A 

Review, Clinical Immunology, Volume 215, 2020, 108427,  ISSN 1521-6616,https://doi.org/10.1016/j.clim.2020.108427.(https://www.sciencedirect.com/science/article/pii/S152166162030262X)

2. Wherry, E. John, and Dan H. Barouch. “T Cell Immunity to Covid-19 Vaccines.”

 Science, vol. 377, no. 6608, 2022, pp. 821–822., https://doi.org/10.1126/science.add2897.

Assignment 4: End-of-term Reflection

Immunology is the study of the immune system and the mechanisms of how it protects organisms from infection. This class was useful to my career path because I intend on becoming a veterinarian. It is important to know how the immune system fights off certain illnesses and how different medications help aid the immune system on a cellular level. One class that this material helped me with in particular was Histology. In histology, we learned about the tissues of the lymph organs, which are vital in immune cell maturation. Immunology gave me the basic knowledge of what cells are located in these organs and why they are important, making learning the histology material easier.