A rapidly increasing area of immunotherapy is the role of immunogenomic cellular and genetic editing and replacement procedures and cell transplantation therapies. Specifically, transplantation procedures include direct and cell-based stem cell therapy (“regenerative medicine”); immunogenetic and immunogenomic procedures (molecular biology), namely gene replacement procedures including the CAR-T or CAAR-T cell therapies; and gene editing procedures including CRISPR-Cas9 (and 13) therapies. They are targeted, organ-specific treatments (stem cells) as well as disseminated and genomic therapies (CRISPR and CAR-T) with somewhat similar applications but different therapeutic goals in autoimmune diseases, genetic disorders, cancers, and numerous other congenital, acquired, and chronic conditions. These innovative and “disruptive” biomedical and cellular therapies enjoy the benefits that piggyback on the successes of other genetic and cancer treatments and vice versa. The impact of these procedures (and their complexities) are of such consequence to immunotherapy that each deserves its own blog. So let’s start with stem cell therapies and then address each subsequent procedure in detail in separate blogs.
Stem cells are cells within the body originating during embryologic development (from totipotent to pluripotent embryonic stem [ES] cells). During early life and growth, these undifferentiated ES cells have the potential to develop into many (and any) different types of adult (somatic) stem cells found in organs and tissues in the body. They also differentiate into red blood cells (erythrocytes), platelets, leukocytes (WBCs), and lymphocytes or immune cells (Figure 5.2). Adult stem cells serve as a repair system for the body. In some organs, such as the gut and bone marrow, they regularly divide to repair and replace worn-out or damaged tissues. When these cells (particularly the more versatile human embryonic, pluripotent [PSC]) are used in cell-based therapies to treat disease, they are referred to as regenerative or reparative medicine.
The clinical value of stem cells lies in the differentiation of embryonic (pluripotent) stem cells into differentiated adult stem cells essential in the repair and regeneration of normal healthy tissue, but also in a more sinister role in cells differentiating into disease-oriented progenitors. But, perhaps the most important potential application of human stem cells is the generation of cells and tissues that could be used for cell-based therapies (“stem-cell transplantation”). Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and RA.
Stem cells can be readily harvested from bone marrow (called bone marrow transplant) and adipose tissue (a bountiful source of stem cells) and other bodily tissues. They are then converted into undifferentiated induced pluripotent cells (iPSCs) suitable for transplantation into diseased and degenerated organs and body structures (e.g., diabetes, osteoarthritis, etc.). These iPSC cells then regenerate and begin to replace the abnormal cells with new, normal cells and even potentially functioning organs (organ morphogenesis) (Figure 5.2). Currently, muscle and bone tissue are particularly amenable to cell and tissue regeneration.
Stem cell transplantation procedures include a number of methods to deliver targeted therapeutic genes through direct delivery and/or cell delivery (Fig. 5.3). Direct delivery packages the gene into a vehicle such as a genetically engineered retrovirus that is injected into the patient, whereupon it penetrates the genome and thus, the therapeutic gene is delivered to the targeted organ system. The weakness of this method of delivery includes the random integration of the gene into the patient’s chromosomes with unknown potential adverse effects. Conversely, the cell delivery method removes cells from the patient (embryonic stem cells [ES], HLA, or somatic cell nuclear transfer [SCNT]) and introduces the “packaged gene” in the cells (in vitro, i.e., in a test tube) and returns them back into the patient. The use of undifferentiated ES cells as the vehicle for gene retransplant to the patient (autologous transplantation) offers additional specificity to the process where the ES cells can replicate only in the target organ.
The objective of stem cell transplantation therapy in immunology is to destroy the mature, long-lived, and auto-reactive immune cells and generate a new, properly functioning immune system. This process has enormous potential in autoimmune diseases, cancers, and other hereditary and acquired genetic mutations resulting in immune system compromise. The patient’s stem cells are used in a procedure known as autologous (from “one’s self”) hematopoietic stem cell transplantation. First, patients receive injections of a growth factor, that coaxes large numbers of hematopoietic stem cells to be released from the bone marrow into the bloodstream. These cells are harvested from the blood, purified away from mature immune cells, and stored. After sufficient quantities of these cells are obtained, the patient undergoes a regimen of cytotoxic (cell-killing) drug and/or radiation therapy, that eliminates the mature immune cells. Then, the hematopoietic stem cells are returned to the patient via a blood transfusion into the circulation where they migrate to the bone marrow and begin to differentiate becoming mature immune cells. The body’s immune system is then restored.
Discussion Questions:
Among the multiple forms of human stem cells, the pluripotent category is the most valuable in stem cell transplantation. Why is that so and give specific examples?
Explain how stem cell transplantation can be used to treat an autoimmune disease.
Comments