PL1003 - Topic 4 - Lecture 4.4 - Tolerance and Immunotherapy Lecture Notes PDF

Immunological Tolerance and Immunotherapy Janine Coombes, [email protected]  Learning outcomes Define the concept of immunological tolerance, and briefly explain how central and peripheral mechanisms of tolerance operate. Give examples of different ways that the immune...

Immunological Tolerance and Immunotherapy Janine Coombes, [email protected]  Learning outcomes Define the concept of immunological tolerance, and briefly explain how central and peripheral mechanisms of tolerance operate. Give examples of different ways that the immune system can become dysfunctional. Explain, with examples, how different immunotherapeutic approaches can be used to treat human disease. 20 November 2 2024  Antigens: Self and Non-Self Antigens can be foreign (e.g. belonging to a pathogenic microbe). Or “self” (proteins from our own bodies). Antigen Presenting Cells will process and present both kinds of antigen to T cells. BUT we have multiple mechanisms to ensure that our immune system does not launch an attack against “self” antigens. This would lead to destruction of host tissues. 20 November 3 2024 Antigen recognition: diversity and self / non-self discrimination Lymphocytes carry millions of different antigen receptors, each recognising a specific antigen. How is this diversity generated? By randomly recombining segments of the genes encoding the receptor molecules, millions of different variants of the gene can be generated, resulting in millions of different antigen receptor specificities. Antigen recognition: diversity and self / non-self discrimination Some of these receptors will recognise self-antigens. The removal of cells bearing these receptors is a crucial step in allowing for self /non-self recognition (self tolerance). This occurs during B cell development in the bone marrow, and during T cell development in the thymus. Left with repertoire of T and B cell receptors recognising foreign antigens. During an immune response, lymphocytes that bind their specific antigen will proliferate and differentiate into effector cells. Immunological Tolerance A state of unresponsiveness to a particular antigen e.g. self antigen Central or Peripheral Anergy (unresponsiveness) e.g. deletion of self- Apoptosis (death) reactive T cells in the Active suppression (Regulatory T cells) thymus Tolerogenic antigen presentation Inhibitory ligands  send negative signal Immune to T cell suppressi ve cytokines Reduced co- stimulatory molecules (no signal 2) Ochando et al: https://doi.org/10.1111/tri.13504 Autoimmunity What would happen if we didn’t remove or inactivate T cells with receptors that recognise self-antigens? Rheumatoid Arthritis Systemic Lupus Erythematosus Multiple Sclerosis Psoriasis Etc. Tumour Immune Evasion To avoid attack from the immune system, tumor cells develop different strategies to suppress the immune response. Immunotherapy can be used to overcome tumour immune evasion / suppression.  Immunotherapy / Biologics Treating disease by modulating immune responses (enhance or suppress) Rapidly growing field. Small molecules, proteins, cells. 20 November 10 2024  Examples of Immunotherapy Checkpoint inhibitors (CTLA-4, PD-L1/PD-1) Cytokines (GM-CSF, Type 1 Interferon) CAR T-cell therapy (e.g. CD19 B-ALL) Monoclonal antibodies (Tocilizumab/IL-6R, Adalimumab/TNFα, Rituximab/CD19) Dendritic Cell Vaccine Therapy Oncolytic viruses 20 November 11 2024  Recombinant Cytokines Granulocyte Monocyte Colony Stimulating Factor (GM-CSF) Sargramostim/Leukine Stimulates generation of immune cells (neutrophils, monocytes, macrophages, DCs) Used to help regenerate immune function after a bone marrow transplant. 20 November Front. Immunol., 17 August 2021 | https://doi.org/10.3389/fimmu.2021.706186 12 2024  Checkpoint Inhibitors Tumour cells can express a protein on their surface called PD-L1. PD-L1 binds to PD-1 on T cells This sends a negative signal to the T cell, inactivating it. PD-L1/PD-1 inhibitors (e.g durvalumab, atezolizumab, avelumab) can release this https://creativecommons.org/licenses/by/4.0/ inhibition, allowing the T 20 November 13 2024  CAR T cell therapy Used to treat B cell Acute Lymphoblastic Leukaemia (B-ALL) The patients T cells are genetically modified to express a chimeric antigen receptor (CAR) Recognizes a protein antigen on the surface of A virus is used to introduce leukaemia cells WITHOUT new DNA into the T cell, the need for processing encoding the chimeric and presentation on MHC antigen receptor (CAR) molecules. Hucks, G., Rheingold, S.R. The journey to CAR T cell therapy: the pediatric and young adult 20 November 2024This directly instructs the T experience with relapsed or refractory B-ALL. Blood Cancer Journal 9, 10 (2019). http://creativecommons.org/licenses/by/4.0/.14  Monoclonal Antibodies E.g. Adalimumab (Humira) Binds to a pro-inflammatory cytokine, TNFα. Prevents the cytokine from promoting inflammation. Used to treat various autoimmune and inflammatory conditions: rheumatoid arthritis, Crohn’s disease, plaque psoriasis…. Increases risk of infection and tumours. 20 November 15 2024