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81 Cards in this Set

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What is a Chimerism?
A combination of two animals into one, having more than one genetically distinct cell population.
What is the primary reason for tissue and graft rejection?
Because the MHC cell surface proteins are encoded by genes that are incompatible between the donor and recipient.
How many HLA proteins do humans express?
12:
Two each of the three Class I
Two each of the three Class II
What is more antigenic in an allogeneic recipient; the donor's protein antigens, or their MHC proteins?
The MHC molecules!
What is the basis of MHC alloreactivity?
Degeneracy/promiscuity of the Tcell receptor, and polyspecificity.
What is TCR degeneracy?
The ability of a TCR to react with more than one ligand.
What does TCR Promiscuity refer to?
The ability of one's TCells to react to foreign MHC; we thought they were self restricted!
What is Polyspecificity?
The ability of one's Tcells to react to not only foreign MHC, but also foreign peptide.
What are the 2 pathways of Allorecognition?
1. Direct allorecognition
2. Indirect allorecognition
What is Direct Allorecognition?
An APC in the graft presents foreign peptide on its foreign MHC to our own TCRs.
What is Indirect Allorecognition?
Our own APC presents foreign peptide on our own MHC.
What type of foreign protein from a graft is most antigenic even when presented indirectly?
MHC and miHA
What type of rejection does direct allorecognition play more of a role in? Indirect?
Direct: acute
Indirect: chronic
What are minor HA's?
Endogenous (to donor) self peptides that occupy the binding groove of MHC molecules.
What is the main determinant for whether a self-donor-peptide might be minor HA?
Genetic polymorphism
How do minor HA's compare to Major?
They are much less potent in stimulating graft rejection.
What is the source of the vast majority of polymorphisms in miHAs?
SNP's within the human genome.
What does it mean to say that minor HA's are cumulative in their effect?
Multiple proteins with polymorphism (miHAs) can elicit graft rejection equivalent to MHC mismatch.
What are 3 types of miHA?
-Immunodominant (most Agic)
-Subdominant
-Cryptic
Does HLA matching include miHA's within its process?
No, it does nothing to match the minor HA's.
What does HA stand for?
It's the patient's initials.
What is the prototypical miHA?
The proteins encoded on the Y chromosome - transplanted skin from males to females causes rejection.
Why don't females tolerate proteins on the Y chromosome?
Because they're not there during negative selection.
What was the first H-Y miHA to be molecularly defined?
SMCY
What type of MHC is SMCY restricted to?
MHC class I
What is HA-2?
The first human miHA to be cloned and sequenced.
What type of cells recognize HA-2?
CD8 Tcytotoxic cells
What type of miHA is HA-2?
Immunodominant
What are the 3 mechanisms of graft rejection?
1. Hyperacute
2. Acute
3. Chronic
What is the cause of hyperacute rejection?
Preformed antibodies (mostly against RBC antigens) that activate complement and cause inflammation/thrombosis.
What is another name for hyperacute rejection?
White graft
What is responsible for Acute rejection?
Tcell mediated damage and inflammation, and maybe allospecific antibodies.
What is responsible for Chronic rejection?
Chronic delayed type hypersensitivity (cellmediated) reactions
What are the 2 common findings in chronic rejection?
-Graft arteriosclerosis
-Vessel occlusion
How would we develop pre-formed antibodies to a graft?
By exposure to certain microbes that express mimicry antigens.
What are the 3 phases of acute graft rejection?
1. Recognition/afferent
2. Amplification/central
3. Effector/efferent
What happens in the Recognition phase of acute rejection?
Donated APCs from the graft travel to nearby lymph nodes.
What happens in the Amplification phase of acute rejection?
The donated APCs present their peptides via the Direct pathway to recipient T/B cells
What happens in the Effector phase of acute graft rejection?
The primed host T/B cells travel back to the site of "injury" or graft and attack it.
What is currently more of a problem in kidney grafts; acute or chronic rejection?
Chronic
Why is chronic rejection so bad?
It is irreversible and leads to end-stage renal disease!
True/false: 50% of kidney allografts will need replacmnt after 10 years because of chronic rejection?
True
3 strategies for preventing ACUTE graft rejection by blocking signal 1:
1. OKT3
2. Cyclosporine
3. Tacrolimus
What does cyclosporine inhibit exactly?
The calcineurin pathway
3 strategies for preventing ACUTE graft rejection by blocking signal 2:
-Steroids
-CTLA4-Ig
-Anti-CD40L
3 strategies for preventing ACUTE graft rejection by blocking signal 3:
-Sirolimus
-Anti-CD25 mAb
-ONTAK
-JAK/STAT inhibitors
How come we don't really match tissues for transplant anymore?
Because immunosuppression overides both the benefits and effects of matching.
What are 3 general types of adverse effects of immunosuppression?
1. Infections
2. Spontaneous neoplasms
3. Toxicity
What is PTLD?
Post transplant lymphoproliferative disease - the common side effect of immunosuppression.
What is the ultimate goal in organ transplantation?
To induce organ/graft specific immune tolerance.
What are 2 possible ways to induce tolerance?
1. By harnessing negative selection in central tolerance
2. By inhibiting the co-stim signal; peripheral tolerance.
Regardless of whether you use central or peripheral tolerance mechanisms, what is necessary to maintain tolerance once induced?
Tregulatory cells
How would you achieve co-stimulatory blockade?
By giving anti-CD40L or CTLA4-Ig
What is the cure for radiation sickness?
Bone marrow transplant
What does transplanting hematopoietic stem cells provide?
A lifelong supply of cells that can become many lineages, at a rate of up to one trillion per day.
What are 3 sources of HSCs?
-Bone marrow
-Peripheral blood
-Placental cord blood
What is the most immunologically naieve?
Placental
What are 3 types of HSC donors?
-Autologous
-Allogeneic
-Xenogeneic
Which type of donor is the best in terms of prognosis?
Autologous
What is an autologous BMT done for?
Treating cancer with higher doses of chemoradiotherapy.
What two things have to be done for an allogeneic BMT that don't for autologous?
-Pretransplant conditioning
-Immunosuppression
What does pretransplant conditioning consist of?
-Tumor elimination
-Myeloablation to create space for the graft
What is the purpose of pre-transplant immunosuppression in an allogeneic BMT?
To prevent graft rejection
What is the purpose of post-transplant immunosuppression in an allogeneic BMT?
To prevent GVHD
What are the major obstacles in allogeneic BMT?
-Finding suitable donor
-Preventing graft rejection
-Preventing GVHD
-Infections, slow immune recovery
-Relapse
-Transplant toxicity
What is the best/most ideal HSCT donor?
An identical twin or autologous donor
What is 2nd best? 3rd?
2. A genotypically HLA identical sibling
3. A phenotypically HLA identical sibling
What is better; a partially matched family member, or fully matched unrelated donor?
Partially matched FAMIlY donor
What's better, a partially matched unrelated donor, or a haplotypte mismatched parent?
Partially matched unrelated donor
What is the worst type of donor?
A full mismatch of all 12 HLA alleles.
What IS GVHD?
The reaction of grafted Tcells against host HLA antigens.
What is ACUTE GVHD?
A reaction soon after transplant where mature donor Tcells recognize and react against host antigens.
What is CHRONIC GVHD?
A late complication that is like autoimmune disease
When does Chronic GVHD occur?
100 days after transplant or more
What is chronic GVHD thought to result from?
Cytokine and Tcell dysregulation
What 3 organ systems suffer in acute GVHD?
-Skin
-Liver
-GI tract
When MHC I and II are matched and the GVHD is caused by miHA antigens, what Tcells will be involved?
ALWAYS CD8, sometimes CD4
What is the most effective way to prevent acute GVHD?
Tcell depletion
Do you want to deplete ALL of the Tcells from a BMT or HSCT?
No
Why do you need Tcells in a graft?
1. For donor engraftment
2. For graft vs leukemia effect
3. For immune recovery
What are 3 types of prophylatic therapy to prevent Unacceptable GVH reactions from starting?
-Cyclosporine
-Methotrexate
-Steroids