Transplant lecture (young)

Adjuvant

• An agent added to a vaccine to enhance immune responses against vaccine antigens
• Used for over 80 years
• Technology is constantly evolving due to advances in immunology and chemistry
• Recombinant proteins and peptides can be poorly immunogenic

Different Adjuvants - Different Strategies

• Delivery: Carriers stabilize vaccine antigens, allowing them to remain present for extended periods.
• Immune potentiator: Exerts a direct stimulatory effect on immune cells, initiating the immune response through the activation of innate immunity. A danger signal is involved.

The "Perfect" Adjuvant

• A perfect adjuvant involves both delivery and immune potentiator strategies
• Delivery enhances antigen reaching immune cells
• Immune potentiator directly activates these cells
• The goal is to activate only necessary immune response elements for protection, avoiding generalized immune activation, or an "effective and safe" response.

Alums

• Primarily aluminum adjuvants
• Used extensively in veterinary vaccines.
• Common adjuvant in human vaccines
• Induces strong Th2 responses
• Examples:
  • Aluminum hydroxide
  • Aluminum potassium sulfate (often called "Alum")
• Used in many toxoid formulations (e.g., Clostridial vaccines)

Lipid/Oil Emulsions

• Detergent-stabilized emulsions of oil and water
• Precise mode of action is not entirely understood
• Depot effect
• Induces MHC responses
• Primarily used in veterinary vaccines
• Gaining acceptance in human vaccine formulations (e.g., MF59)
• Three basic forms:
  • Oil in water (O/W)
  • Water in oil (W/O) (Freund's)
  • Water in oil in water (W/O/W)

Oil Based Adjuvants Used in Veterinary Vaccines

• Water-in-oil emulsions (W/O): Antigen-containing water droplets within a continuous oil phase.
• Oil-in-water emulsions (O/W): Emulsified oil droplets within a continuous antigen-containing aqueous phase.
• Water-in-oil-in-water emulsions (W/O/W): Antigen-containing water droplets within larger oil droplets, dispersed in a continuous antigen-containing water phase

W/O/W Adjuvant System

• Diagram showing oil phase, aqueous phase and antigens
• Surfactant is indicated

PRR and Other Ligands

• Microbial Derivatives:
  • PAMPs induce Th1 response
  • LPS interacts with APCs, releasing pro-inflammatory cytokines
  • CpG is bacterial DNA
• Mucosal:
  • Heat-labile E. coli enterotoxin (LT)
  • Cholera toxin (CT)
• Saponins:
  • Plant derivative
  • Primary function is cytokine induction
  • Potentiates Th1 response (IL-2, IFN-γ, IgG2a).
  • Can be toxic to certain species (e.g., humans, mice)
  • Commonly used in veterinary vaccines

Delivery Vehicles

• Liposomes: Membrane-bound phospholipid vesicles, trapping or incorporating antigen in their lumen or membrane
• Increased antigen uptake by antigen-presenting cells (APCs)
• ISCOMs (Immune Stimulating Complexes): Liposomes containing saponin
• Virosomes: Liposomes prepared from viral membranes
• Virus-like Particles (VLPs): 30-90 nm self-assembled virus proteins with a nucleic acid or lipid genome

Vaccine Side Effects

• Typically include redness/pain at injection site, sneezing/nasal congestion (intranasal), fatigue/headaches
• Monitor adverse reactions using the Vaccine Adverse Events Reporting System (VAERS)
• Urban Legends:
  • DTaP associated with sudden infant death syndrome (SIDS)
  • HBV associated with multiple sclerosis
  • Inactivated poliovirus vaccine (IPV) contamination with SV40 associated with cancer
  • Polio vaccine associated with HIV
  • Lyme disease vaccine associated with arthritis

Future Vaccines

• Prophylactic: HIV, Ebola, Hepatitis C virus, malaria
• Therapeutic: Cancer, dendritic cell culture, autoimmune/allergy, domestic animal castration

Summary

• Whole organism (modified live, inactivated)
• Subunit
• Recombinant Live
• DNA
• Adjuvant
• Vaccine Usage
• Vaccine side effect outweigh disease

Types of Vaccines and Their Pros and Cons

• Information on vaccine types, their features, advantages, and disadvantages

Transplantation

• The Nature of Transplantation:
  • Molecular basis of graft rejection
  • Allo/auto antigens, minor histocompatibility antigens
  • Solid organ transplants
  • Graft rejection, graft-versus-host disease
• Therapy:
  • Pre-therapy screening
  • Post-transplant drugs
  • Tolerance
  • Stem cell transplantation
  • Use
  • Rejection
  • Graft-versus-host
  • Transfusions

Terminology

• Syngeneic: Grafts between genetically identical individuals
• Allogeneic: Grafts between genetically diverse individuals
• Autograft: Self-tissue transplanted to a different site (e.g., skin grafts in burns)
• Isograft: Tissue transferred between genetically identical individuals (mostly experimental)
• Allograft: Tissue transferred between genetically different individuals of the same species (most common)
• Xenograft: Tissue transferred between different species (experimental)

Tissue Antigens

• Graft rejection is due to differences in HLA/MHC haplotypes between recipient and donor.
• Rejection involves both T and B cell responses

Molecular Basis of Graft Rejection

• Immune response against grafts follows general immune response rules and processes
• Recognition occurs via MHC-mediated recognition of “altered self” or disparate MHC antigens (allorecognition), or through recognition of minor histocompatibility antigens

Direct Recognition

• T-cell positive/negative selection ability to recognize self-MHC at a certain level
• Peptide addition specifies recognition for normal tissues (altered-self)
• Foreign MHC molecules can resemble self but be different enough to trigger T-cell activation
• Passenger leukocytes in grafts can stimulate recipient T cells.

Indirect Allorecognition

• More direct stimulation
• Foreign peptides are the result of antigens shed by grafts (e.g., dying cells)
• Self-proteins won't be recognized
• Some all-MHC proteins can produce immunostimulatory T cell peptides

Minor Histocompatibility Antigens

• Minor histocompatibility antigens (MiHAs) typically cause chronic rejection or a slower response.
• Differences in allelic coding for similar proteins between donor and recipient can cause an immune response.
• Example: the protein coding for blue eyes on the graft could provoke a response in a recipient with brown eyes.

Solid Organ Transplantation

• Note that transplantation is naturally a traumatic experience, damaging tissues and endothelium.
• This damages tissue, endothelium, blood vessels, activating DAMPs and PAMPs on the graft, triggering innate immune responses.

Adaptive Immune Responses

• Pre-formed antibodies can directly kill graft tissue (hyperacute rejection).
• Passenger antigens and leukocytes are transported to lymph nodes, initiating germinal center formation and cellular activation.
• CTLs, antibodies and helper T cells produced against the graft can travel to and destroy affected tissue as a foreign body.

Terminology Cont'd

• Hyperacute rejection: Occurs in minutes due to the existence of preformed antibodies
• Acute rejection: Occurs within days/weeks due to a normal immune response.
• Chronic rejection: Occurs over months/years; mechanisms are not entirely understood.

Types of Rejection of Solid Organ Transplants

• Summary table of rejection types, including time, targets, mechanisms, cells infiltrating, fibrosis and treatments.

Graft-Versus-Host Disease

• Occurs when graft leukocytes fail to recognize the recipient's tissues (leading to an immune attack on host tissues).
• Immune processes involved are as expected
• Dendritic cells and T cells within the transplanted organ are capable of proliferating and attacking host tissues.
• More common with transplants of immune tissues (e.g., blood, stem cells) compared to solid organs.

Minimizing Graft Rejection

• Matching donor and recipient HLA/MHC haplotypes is the most effective way to prevent rejection
• In the past, this was done with Mixed Lymphocyte Cultures (MLCs) testing
• Flow cytometry is now commonly used to determine donor and recipient HLA allele-specific leukocytes

Screening for Pre-existing Antibodies

• Determining if pre-existing antibodies in the recipient could affect graft success
• Repeat transplants have lower success rates due to memory response
• Screening can use solid-phase or flow cytometry analysis to look for recipient immune responses to donor cells

Immunosuppressive Therapy

• Immunosuppressive medications generally "turn off" the recipient's immune response, preventing their immune cells from attacking the implanted organ.
• Cyclosporin A initially was commonly used to block IL-2-dependent proliferation, but there are more modern analogs with fewer side effects.

Induction of Graft Tolerance

• Highly targeted methods are being developed to limit transplant rejection by inducing immunological tolerance.
• Goal is to convince the immune system that the new organ is self so the rejection response does not happen.
• Method involves selectively inhibiting or stimulating regulatory T-cells.

Hematopoietic Stem Cells

• Hematopoietic stem cell transplantation (HSCT) is used in treating various conditions.
• Radiation/chemotherapy used in HSCT destroys immune cells in the body.
• Can be used in the effort to treat autoimmune disease or to enhance organ transplant acceptance

Blood Transfusions

• Blood transfusions, one of the first forms of organ transplantation, require careful ABO blood typing in order to prevent immune rejection due to pre-existing antibodies directed against donor blood cells.
• If pre-existing recipient antibodies are not accounted for, the donor cells may be attacked, leading to toxicity and anemia.

Blood Group Antigens/Antibodies

• Table showing blood types, genotypes, RBC antigens, antibodies and compatible donors

Next (final) lecture

• Autoimmunity

Test your knowledge on graft-versus-host disease, HLA matching, and immunosuppressive drugs. This quiz covers various aspects of graft tolerance and vaccine adjuvants, focusing on the immune response mechanisms involved. Perfect for students of immunology or medical professionals.