Blood Transfusions and Tissue Typing
Consequences of mismatched blood transfusions
When someone receives the wrong blood type, their immune system treats the donor red blood cells as foreign invaders. The resulting immune response can range from mild to fatal.
- Agglutination occurs when antibodies bind to mismatched antigens on donor red blood cells, causing them to clump together. This is most commonly seen with ABO blood group mismatches.
- Hemolysis is the rupture of those clumped red blood cells, releasing free hemoglobin into the bloodstream. Rh incompatibility is a classic trigger for hemolytic reactions.
- Transfusion reactions are the broader immune-mediated response, producing symptoms like fever, chills, flank pain, and kidney damage as free hemoglobin clogs the renal tubules.
- In severe cases, mismatched transfusions can trigger disseminated intravascular coagulation (DIC), where widespread clotting uses up clotting factors and leads to uncontrolled bleeding, potentially causing multiple organ failure.
Tissue typing for organ transplantation
Organ transplants fail when the recipient's immune system recognizes the donor organ as "non-self" and attacks it. Tissue typing exists to minimize that risk by matching key surface proteins between donor and recipient.
Those surface proteins are human leukocyte antigens (HLAs), which are the human version of the major histocompatibility complex (MHC). HLAs sit on cell surfaces and present peptide fragments to T cells, so the closer the HLA match, the less likely the recipient's T cells are to mount an attack.
- Class I HLAs (A, B, and C) are found on all nucleated cells. These present intracellular peptides to cytotoxic T cells.
- Class II HLAs (DP, DQ, and DR) are found on antigen-presenting cells like macrophages and dendritic cells. These present extracellular peptides to helper T cells.
Even with good tissue matching, recipients almost always need immunosuppressant medications to prevent rejection:
- Calcineurin inhibitors (cyclosporine, tacrolimus) block T-cell activation and proliferation
- Antiproliferative agents (mycophenolate mofetil, azathioprine) inhibit lymphocyte division
- Corticosteroids (prednisone) broadly reduce inflammation and suppress immune responses
The tradeoff with immunosuppressants is real: suppressing the immune system enough to protect the graft also increases vulnerability to infections and certain cancers. Finding the right balance is an ongoing clinical challenge.
Graft-versus-host disease (GVHD) is a unique complication, especially in stem cell transplants. Here, the donor's immune cells attack the recipient's tissues, essentially reversing the usual rejection scenario.
Types of transplants
- Allografts are transplants between genetically different individuals of the same species. This is the most common type in clinical medicine (kidney from an unrelated donor, for example).
- Xenografts involve transplanting organs or tissues between different species (such as pig heart valves into humans). These pose major immunological challenges because the species differences in surface antigens trigger intense rejection responses.
Cancer Immunology and Immunotherapies
Immune system vs cancer
Your immune system constantly patrols for abnormal cells, a process called immune surveillance. Both branches of immunity contribute:
- The innate immune response provides the first, non-specific line of defense. Natural killer (NK) cells are especially important here because they can destroy cells that have lost their MHC class I markers, a common feature of cancer cells. Macrophages also phagocytose tumor cells and present their antigens to activate adaptive immunity.
- The adaptive immune response mounts a targeted attack. Cytotoxic T lymphocytes (CTLs) directly kill cancer cells by recognizing tumor antigens presented on MHC class I. B cells produce antibodies that bind cancer cell antigens and promote antibody-dependent cell-mediated cytotoxicity (ADCC), where NK cells destroy the antibody-tagged cancer cell.
How cancer cells evade immunity
Despite immune surveillance, tumors still develop because cancer cells evolve ways to dodge the immune system:
- Downregulating MHC class I molecules so CTLs can no longer recognize them
- Secreting immunosuppressive factors like TGF-β and IL-10 that dampen immune cell activity in the surrounding area
- Recruiting regulatory T cells (Tregs) that actively suppress nearby immune responses
- Shaping the tumor microenvironment into an immunosuppressive zone where immune cells are inhibited or reprogrammed to support tumor growth
This ongoing battle between the immune system and cancer is described by the concept of immunoediting, which unfolds in three phases:
- Elimination — the immune system successfully detects and destroys cancer cells
- Equilibrium — the immune system contains but can't fully eliminate the tumor; cancer cells and immunity are in a standoff
- Escape — cancer cells that survived selection pressure have acquired enough evasion tricks to grow unchecked
Cancer immunotherapies
These treatments work by boosting or redirecting the immune system's ability to fight cancer:
- Checkpoint inhibitors are antibodies that block the "off switches" on T cells (CTLA-4, PD-1, or PD-L1). Cancer cells often exploit these checkpoints to shut down T-cell attacks. Blocking them releases the brakes on the immune response.
- Adoptive cell therapy involves collecting immune cells, expanding or engineering them outside the body, then infusing them back into the patient. CAR T-cell therapy is a well-known example where a patient's T cells are genetically modified to express receptors that recognize specific tumor antigens. Tumor-infiltrating lymphocytes (TILs) can also be harvested, expanded, and reinfused.
- Cancer vaccines expose the immune system to tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) to prime an anti-tumor response. Unlike preventive vaccines, these are typically therapeutic, given after cancer has developed.
- Oncolytic viruses are engineered viruses that selectively infect and lyse cancer cells while leaving normal cells intact. As the cancer cells burst, they release tumor antigens that further stimulate the immune response against the tumor.