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Manipulation of Immunology
n/a
23
Medical
Graduate
04/18/2011

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Term

hyperacute rejection (organ transplants) -how can these complement fixing Ab be generated? -why is it so fast?

-what type of hypersensitivity rxn is it?

Definition
Type III fast, sometimes before operation is complete pre-formed, complement fixing Ab against blood group or HLA I -HLA-II can play a role b/c of upregulation of Class II Ag in the inflamed state of the donor graft and recipient Complement fixing Ab bind to vascular endothelium initiating complement & coagulation cascade Vasculature clots & leaks -initially pale then purple from hemorrhage, eventually ischemia Irreversible how generated? pregnancy, blood transfusion (HLA not assessed), previous transplants fast b/c it involves *complement*
Term
Understand the process of attenuation and the risks/benefits of attenuated vaccines

*which vaccines are LAV*
Definition
live organisms mutated to reduce pathogenicity; can be done by growing viruses on non-human cell lines/animals; can also be done by genetic engineering

benefits:
strong immune response, can mimic natural disease process,immunity is generated to target the infectious process - includes route of infxn

risks:
can cause problems in immunocompromised
pts, chance of reversion to pathogenic form

measles, mumps, polio (Sabin), yellow fever
Term
What's a subunit vaccine?
Definition
use surface components of viruses or bacteria
-Hepatitis B virus is purified from blood from pts or recombinant pr
-Encapsulated bact - Ab responses against CAPSULAR POLYSACCHARIDES are protective - capsular polysaccharides can provoke T independent B cell responses, but not very immunogenic
Term
Define conjugate vaccines and understand the mechanisms for generating protection against bacteria
Definition
these vaccines conjugate toxoid to polysaccharide, converts to T dependent Ag
Term
Define an adjuvant and understand their uses
-Freund's complete adjuvant
-Aluminum hydroxide
Definition
Killed/non-viable vaccines aren't very immunogenic themselves, require adjuvant to enhance immunity

adjuvants are substances that induce inflammation by Ag-dependent mechanisms, enhance vaccinations

*a good adaptive immune response REQUIRES a state of inflammation* due to macrophage activation & recruitment of inflammatory cells

Freund's: emulsion of killed mycobacteria and mineral oil

Alum: only approved adjuvant in U.S., tends to promote *Th2-type* responses
Term
Know the challenges to vaccine design and improvement
-3 points

Challenges
Definition
Understand disease pathogenesis better to identify targets
-*recombinant DNA technology* - use to produce purified vaccine proteins (HBV-HBsAg) or reduce virulence (Salmonella)

understand *how the immune system best protects* from infections disease
-Th1 vs Th2: addition of IL-12 can promote Th1
-route of immunization-site of infection

*improve adjuvants*
-ISCOMS - immune stimulatory complexes
lipid molecules carrying class I restricted poly/peptides fuse with cell membrane, deliver them to cytoplasm
-cytokines as molecular adjuvants (GM-CSF, IL-2)

pathogens that provoke weak immune responses, that have large numbers of strains, that evade immune response and elicit chronic illness
Term
Know the difference between autograft, xenograft, isograft and allograft
Definition
auto: graft from self
xeno: graft from different species
iso: from identical twin
allo: from someone else
Term
Understand the importance of blood group matching for blood transfusion and organ transplant
Definition
A,B,O antigens expressed on endothelium of all BV
most solid organs must be matched for blood group to prevent hyperacute rejection
Anti-HLA Ab from previous sensitization (pregnancy, transfusion, transplant) can also cause rejection
Term
Understand the role of the bone marrow transplant and T cells during GVHD
-also GVL, GVT
Definition
In allogeneic transplants graft-vs-host disease (GVHD) occurs
-*mature T cells in transplanted BM* respond to recipient's HLA type
-10-28 days after transplant
-diarrhea, hyperbilirubinemia, erythematous rash
-severity correlates with degree of HLA mismatch

In allogeneic transplants reconstitution of the immune system by donor cells provides improved disease-free survival
-graft vs leukemia (GVL) or tumor (GVT) effect
-requires myeloablative therapy to prevent rejection of donor cells; this destroy's recipient's immune system

Pt is myeloablated, autologous or allogeneic cells are transplanted
-1.5 wks later engraftment begins
-neutrophils, then RBC's, then platelets

new immune system becomes tolerant of host
Term
Acute rejection (organ transplants)
-direct pathway of allorecognition
-indirect pathway of allorecognition
Definition
occurs in days to months; matching donor & recipient MHC improves outcome. Most tissues the major alloantigen will be MHC I
-differences in other antigens (minor histocompatibility Ag), can lead to rejection; rejection not as rapid

Recipient T-cells reactive against non-self HLA I (CD8)/II (CD4) Ag on donor tissue (graft)
-produce effector CD4 & CD8 cells that attack graft

Direct pathway:
-donor dendritic cells are carried to secondary lymphoid tissue, depletion of dendritic cells
-activated recipient T cells recognize allogenic Class I or II molecules with donor peptides
-Th1 cells activate macrophages, CD8 kill

Indirect:
-recognize processed donor material presented by recipient cells
-donor dendritic cells migrate to LT, die
-usually chronic
-the graft cells as they’re replenishing within graft shed Ag that are from donor tissue
-Usually endocytic pathway, macrophage mediated
-membrane fragments of dead dendritic cells are processed, presented by recipient dendritic cells
-stimulate a *CD4* response specific for donor HLA peptides & recipient HLA II
-inflammation, damage to endothelium, thickening of BV walls, damage to vascular supply
Term

chronic rejection

-Ag of which HLA class type incite inflammation? why?

Definition
months-yrs; alloreactive T-cells stimulated by indirect pathway drive Ab response Ab specific for graft *class I Ag* incites inflammation -HLAI Ag is highly expressed on vascular tissue damage to vessel walls --> thickening --> ischemic damage to graft
Term
What are pts who have had a splenectomy susceptible to?
vaccine?
Definition
Blood borne infxn, encapsulated bact, gram neg rod, others

Pneumovax (prophylactic abx therapy), due to reduced levels of opsonins and IgG; otherwise pt only has innate immunity
Term
What must the DPT vaccine undergo (specifically, the pertussis portion) in order to make it effective?
Definition
conjugation to a toxoid - elicits T cell response, opsonization

Ab-FcR --> phagocytic cell engulfs
Term
HPV
Definition
prevents genital warts, cervical cancer

Subunit Vaccine (virus coat proteins)
Term
Subunit vaccine
Definition
use antigenic viral components to direct protective neutralizing Ab

HBV
Term
BCG vaccine
Definition
attenuated strain of bovine TB

PPD skin test: patients may test POSITIVE
Term
what happens during a blood transfusion rxn?
2 reasons that could have caused it?

what is a more serious complication that can arise?
Definition
naturally occurring IgM Ab react to transfused RBC (type II). Doesn't require sensitization

IgE-mast cells -> histamine release (type I)
Ab:Ag:complement causing Ab-mediated inflammation (type II) - recipient responds to allergens in the blood by attacking donor Ag

acute hemolytic rxn -> widespread hemolysis within vasculature from IgM binding to RBC, complement activation -> chills, SOB, urticaria, DIC
Term
In BM transplantation, why must patient and donor have HLA allotypes in common?
Definition
the more they share, the better it works

T cells in the pt's new immune system must be positively selected by thymic epithelial cells expressing the recipient's HLA allotypes, AND
to be activated by infxns, those T cells also need to interact with donor-derived dendritic cells that present pathogen-derived Ag on donor HLA allotypes
Term
Minor histocompatibility antigens
Definition
alloantigens, such as H-Y antigens, in which the allogeneic difference is due to the bound peptide and not to the MHC molecule

e.g. brother receiving a BM transplant from an HLA-identical sister

this is why immunosuppressive drugs are still required, even when MHC is matched
Term
what's a toxoid?
Definition
inactivated toxin

stimulate the generation of toxin-specific neutralizing Ab

purified, treated with formalin

e.g. diptheria or tetanus toxin
Term
ex of a combination vaccine?
Definition
DPT

the immune response to the diphtheria and tetatus toxoids is enhanced by the adjuvant effect of the whole pertussis bacteria, produces a strong inflammatory rxn at the site of infxn
Term
Killed vaccines, whole organisms
Definition
viruses: (Salk polio, influenza, rabies), chemically treated with formalin/heated irradiated
-only viruses whose nucleic acid can be reliably inactivated will work

bacteria: pertussis or cholera - killed organism or extract
Term
what type of vaccine should not be given to an immunocompromised patient?
Definition
live-attenuated virus vaccines
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