L30 - Immunotherapies Flashcards
What is rheumatoid arthritis and its risk factors ? How does it arise?
Pathophysiology of the knee joint
Risk factors: women are 2-4 fold more susceptible due to genes that lead to higher risk
Immune cells infiltrate the sinobiom and it goes to knee joint Risk factors
Initiation and progression of rheumatoid arthritis
Rheumatoid arthritis (RA) starts when the immune system mistakenly attacks the joints. This begins with a loss of tolerance to the body’s own proteins. The immune system makes autoantibodies and activates T and B cells, causing inflammation in the joint lining. Over time, this leads to swelling, pain, and damage to cartilage and bone. The inflammation keeps going, making the disease worse if not treated.
What is TNFa
Tumor Necrosis Factor alpha (TNFo)
• a cytokine involved in systemic inflammation
• mainly produced by activated macrophages and monocytes, but also by other types such as endothelial cells, astrocytes, adipocytes etc.
• TNFa is a pyrogen and can induce fever, cell death and inflammation
• overproduction of TNFa has been implicated in many human diseases: rheumatoid arthritis, psoriasis, inflammatory bowel disease among others
What are some TNFa inhibitors
Chimeric antibody with mouse variable region which binds to TNFa and neutralise activity
How does the immune system detect and kill cancer cells?
• Cancer cells die and release abnormal proteins (neoantigens)
• Dendritic cells (APCs) pick up these antigens
• T cells are activated in the lymph nodes
• Cytotoxic T cells (CTLs) travel through the blood to the tumor
• T cells enter the tumor and recognize cancer cells
• T cells kill the cancer cells
• This cycle can repeat to keep fighting the cancer
How does monoclonal antibodies contribute to tumour therapy?
- target specific protein overexpressed on specific tumour cells
- target proteins normally expressed on certain cell types and also on tumours
Using HER2 on breast cancer cells, how are specific proteins targetted overexpressed on specific tumour cells
• HER2 is a receptor protein found on the surface of some cells, including breast cells.
• It belongs to the EGF receptor family and helps regulate cell growth and division.
• In some breast cancers, HER2 is overexpressed, leading to uncontrolled cell proliferation.
• HER2 is activated by ligands like EGF, which triggers dimerization and signaling pathways (e.g. Ras-MAPK) that promote growth.
• Related growth factors include:
• TGF-α, Amphiregulin (AR), Epiregulin (EPR), Neuregulin (NRG1–4)
• Therapies (like Herceptin) target HER2 to block signaling and stop tumor growth (prevents dimerisation)
How do antibodies like Rituximab treat B cell lymphomas by targeting CD20?
• CD20 is a receptor found on healthy and cancerous B cells (important for B cell development).
• Overexpressed in B cell lymphomas, making it a key target for therapy.
• Monoclonal antibodies like Rituximab, Ofatumumab, Obinutuzumab, etc., bind to CD20 and destroy B cells through:
• ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity): immune cells kill antibody-coated B cells
• CDC (Complement-Dependent Cytotoxicity): triggers complement system to lyse B cells
• Induction of apoptosis (programmed cell death)
• Rituximab is a chimeric antibody (mouse variable region + human constant region), while newer ones like Ofatumumab are more fully human.
• Side effect: can also kill healthy B cells since they also express CD20.
How do cancers acquire immune tolerance
Barriers (stromal cells)
What are tumour antigens
• neoantigens: mutations in normal human proteins and recognized as
‘foreign’ by the immune system
• type I MHC will present peptides in the surface
• recognised as foreign by CD8+T cell (cytotoxic)
• often CD8+T cells require further activation to attack tumour cells
What are the stimulatory and inhibitory signals involved in T cell activation?
Stimulatory Signals:
• CD28 on T cells binds to CD80/CD86 on APCs.
• Promotes T cell activation and proliferation.
Inhibitory Checkpoints:
• CTLA-4 (Cytotoxic T-Lymphocyte Associated Protein 4)
• Competes with CD28 for CD80/CD86.
• Prevents overactivation of T cells early in the immune response.
• PD-1 (Programmed Cell Death Protein 1)
• Binds to PD-L1/PD-L2 on other cells.
• Suppresses T cell activity in tissues, especially tumors.
What is the diff between the 2 inhibitory signals
CTLA4 inhibits another simulatory signal wherase PD1 acts directly
How is T cell response enhanced by monoclonal antibodies
They inhibit PD1 and CTLA 4 so it no longer inhibits
What are CAR T cells
Chimeric antigen receptor T cell
What is the structure of a CAR T cell
-lack TCRa and b chains
- single extracellular domain derived from immunoglobulin VH and VL domains (contains co-stimulatory domains that enhance tumour killing activity of T cells)
How has anti cancer therapy become more personalised
T cells can be edited by CAR T cells binding to specific antigen
