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