Theme 10: Transplants and Immunotherapies Flashcards
What are syngeneic grafts?
Isografts and autografts, usually accepted due to antigenic compatibility
What is alloreactivity?
Th and Tc cells recognize non-self molecules from transplants
What is the timeline for first-set rejection?
Complete within 2 weeks, where memory against the graft is generated
What is the timeline for second-set rejection?
Complete within less than a week
What are paired organs?
Organs which we have 2 of (e.g., kidneys), which is available for living donor transplants and allows for more time to properly match MHCs
Describe the process of histocompatibility assessment
1) ABO blood group must match (antigenic difference = hyperacute rejection)
2) MHC haplotype and minor histocompatibility locus is assessed (parents or siblings are first choice)
3) Cross-match test where recipient serum is checked for presence of Abs that might attack donor cells
What is the minor histocompatibility locus?
Genes coding for receptors on cell surface of donated organs known to give an immunological response
What is histocompatibility?
When tissues are sufficiently similar that no rejection reaction takes place (e.g., identical twins)
What % MHC identity do you share with a parent?
50%, because you inherit one haplotype from each parent
What is the rule of HLA inheritance between siblings?
1) There is a 25% chance of inheriting all of the same HLA as a sibling
2) There is a 25% chance of not inheriting any of the same
3) There is a 50% chance of sharing 1 haplotype with a sibling
What is hyperacute rejection?
1) Immediate damage mediated by preformed antibodies that stimulate complement, resulting in complete rejection within 24 hours
2) Occurs before tissue revascularization
3) Antibodies could recognize and bind ABO or HLA and are often due to past blood transfusions/transplants and past infection (cross-reactivity)
4) Can be avoided via blood typing and cross-matching
What is acute rejection?
1) Mediated by T cells, APCs, and cytokines after initial sensitization to donor alloantigens, beginning after about a week
2) Can be avoided/delayed using immunosuppressive drugs
What are the 2 types of presentation of allogenic MHC?
1) Direct presentation
2) Indirect presentation
What is direct allorecognition?
Donor APCs bearing foreign MHC molecules can engage directly with host T cells, independent of antigens associated
What is indirect allorecognition?
Recipient APCs take up cellular debris/donor cells and display foreign MHC antigens for T cell recognition
What is chronic rejection?
Occurs months or years after resolution of earlier rejection, has unknown inducers and is more resistant to standard immunosuppression
When is tolerance to allografts favoured?
1) When tissues lack alloantigens (like cartilage or heart valves)
2) When preventative measures are taken (e.g., grafting first to privileged immune sites)
3) When Tregs are involved
Describe the process of grafting cells/tissues to privileged sites
1) Privileged sites = hidden from immune surveillance
2) Tolerance to donor alloantigens is induced biologically prior to transfer of donor tissue to the actual site of interest
3) Called mixed hematopoietic chimerism = recipient and donor hematopoietic cells coexist
What is ideal for immunotherapy?
It is ideal to have antigen-specific immunotherapy such that it inhibits reactions to the graft but maintains immune system’s ability to respond to other pathogens
What are some general immunosuppressive therapy for transplantation?
1) Total lymphoid irradiation
2) Azathioprine
3) Cyclophosphamide
4) Fungal metabolites
What is total lymphoid irradiation?
1) Used to treat GvHD or for bone marrow transplants
2) Recipient thymus, spleen, and lymph nodes irradiated to wipe out recipient immune cells
2) Bone marrow is transplanted into recipient and donor stem cells can engraft to form a new immune system safely
What is azathioprine?
Mitotic inhibitor to diminish T and B cell populations and increase the survival of allografts
What is cyclophosphamide?
Inserts into DNA helix, used to treat transplant recipients
What are fungal metabolites?
Inhibit Th cell proliferation and cytokine expression to reduce activation of other effector populations involved in graft rejection
What are some antigen-specific immunosuppressive therapy?
1) mAb to CD3 on T cells
2) mAb to CD25 (IL-2 receptor) to block T cell proliferation
3) mAbs against T cell markers
4) Soluble CTLA-4 fusion proteins (binds B7 to induce anergy)
What is used to prevent fetal hemolytic disease?
Rhogam, when the mother is Rh- and the fetus is Rh+
What are broad-spectrum therapies for autoimmune disease?
1) Strong anti-inflammatory drugs
2) Organ removal (e.g., thymus)
3) Used to reduce symptoms
What are the side effects of anti-inflammatory drugs?
More susceptible to cancer and infection
What are therapies that block steps in the inflammatory process?
1) Drugs that block TNF
2) IL-1 receptor antagonist
3) Chemokine/adhesion molecule blockers
Describe the antigen-specific immunotherapy used to treat type I diabetes
Nanoparticles are coated with proinsulin (one of the target antigens) and a molecule that can deliver a tolerogenic signal to APCs
What was the London Drug Trial Catastrophe?
A CD28 agonist was being developed for treatment of rheumatoid arthritis but ended up activation all T cells
What are the 4 categories of anti-cancer therapies?
1) Chemotherapy (arrest proliferation)
2) Hormonal therapies (interfere with tumor growth)
3) Targeted therapies
4) Immunotherapies
What are some immunotherapies for cancer?
1) Immunotoxins (Ab conjugated to toxic molecules)
2) Vaccines
3) Tumor-specific T cell induction
4) CAR-T
5) Manipulation of costimulatory signals (e.g., blocking inhibitory costimulators)
How is immunodeficiency treated?
Mostly with antibacterials, antivirals, and replacement therapies
What are some replacement therapies for immunodeficiency?
1) mAb or cytokines treatment
2) Hematopoietic stem cell transplantation (bone marrow transplants)
3) Gene therapy
