Week 1: A Complex Defense System

Apr 01, 2022

Hello! My name is Sidharth, and this week I’ll be discussing our bodies’ complex defense system against pathogens that “off-the-shelf” CAR T-cells must overcome.

How do Major Histocompatibility Complexes work?

Major Histocompatibility Complexes (MHC) are crucial to our bodies’ defense system against pathogens. They are protein receptors that appear on the membranes of cells. MHC I complexes present antigens (fragments of the pathogen) to cytotoxic (killer) T cells and MHC II complexes present antigens to helper T cells that will recruit other members of the immune system to attack the pathogen. MHC complexes are present in almost every cell of the body; most normal cells express MHC I complexes that label them as “self”. So, in addition to identifying the enemy, MHC molecules act as the “flag” of the immune system, marking a distinction between foreign cells and the cells of a particular individual. Natural Killer (NK) cells are the surveillance team of the immune system, hunting for foreign cells without the proper MHC molecules that are specific to their immune system.

(Note: MHCs are also referred to as Human Leukocyte Antigens (HLA) which are more specific to human cells.)

A computer model of the MHC I protein-antigen complex. (Credit: Science Photo Library)

Deceiving the Immune System

Currently, there are two major types of CAR T-cells: allogenic (from different people) and autologous (from the patient themselves). Autologous CAR T-cells are ideal because they hold the lowest risk of an immune rejection. However, autologous CAR T-cells have numerous problems including the time it takes to manufacture them – time that most patients don’t have. Allogeneic CAR T-cells, on the other hand, hold a high risk of immune rejection and conditions such as Graft v. Host disease. In order to create effective “off-the-shelf” CAR T-cells, researchers must ensure that the cells are not rejected by host NK cells by MHC II receptors or MHC I molecules. Many scientists suggest “knocking-out” the MHC molecules in the CAR T-cells via gene editing methods; however, this poses another problem – an attack by the NK cells.

How can we engineer CAR T-cells that will avoid rejection? The human body has a multitude of defense mechanisms, forcing the need for a perfect ploy to thwart each possible attack.

Thanks for reading – be sure to tune in next week as I delve into solutions.

All the best,

Sidharth

One Reply to “Week 1: A Complex Defense System”

  1. Luc M. says:

    Learning about MHC molecules was fascinating! I look forward to seeing what solutions you come up with regarding CAR T-cells and MHC molecules!

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