Shared Flashcard Set

Details

transplantation immunology
cmbm exam IV
68
Chemistry
Graduate
01/30/2010

Additional Chemistry Flashcards

 


 

Cards

Term
what cells do class I and II MHC present antigen to?
Definition
class I presents antigen from endogenous cells to CD8, class II presents antigen from exogenous cells to CD4
Term
what is MHC restriction?
Definition
peptide antigen is recognized by T cells in the context of class I or II MHC
Term
where are class I and II MHC found?
Definition
class I is found on all cells, class II is limited to just professional APCs
Term
how do the structures of class I and II MHC differ?
Definition
class I has an alpha chain and a beta2 macroglobin, while class II has an alpha and a beta chain with no beta2 macroglobin
Term
how many antigens do MHCs have? which and how many are matched clinically?
Definition
MHCs have 11 antigens (22 codominantly), 3 of which are matched clinically (6 codominantly) b/c they are the most polymorphic. they are HLA-A, HLA-B, and HLA-DR
Term
what are the types of tissue grafts that can be done?
Definition
autograft, isograft, allograft and xenograft
Term
what is an autograft? when is it done? where is the graft taken from? when can this kind of graft be lost?
Definition
this occurs with extensive burns on exposed areas of skin and skin is transplanted from one area of the body to another. generally skin is taken from the inner thighs (less visible areas), and the only time this kind of graft is rejected is if there is an infection
Term
what is an isograft? when does it happen?
Definition
transplant from an identical twin to another identical twin, (genetics should match)
Term
what is an allograft? if you get a graft from a sibling who shares MHC haplotypes with you why will this still require immunosuppressive drugs?
Definition
human-human graft (non identical twin family or unrelated), even if you share both MHC haplotypes with a sibling, you do not match at minor histocompatiblity antigens or other antigens and these can play a role in graft rejection.
Term
what is a xenograft?
Definition
tissue grafts done inbetween species
Term
what is the order of organ transplant ranked by highest number of grafts done? what is the 5-year survival rate
Definition
kidney, liver, heart, pancrease, lung, cornea, bone marrow. the survival rate is between 50-70% (75% for 6 antigen match, less for lower antigen matches)
Term
what happens in the absence of immunosuppressive therapy with allo/xenografts?
Definition
graft rejection
Term
what are the three kinds of graft rejection?
Definition
chronic (now see this the most), acute, hyperacute (shouldn't see this)
Term
what causes graft rejection? how is this proven?
Definition
graft rejection is an immunologic phenomenon. in animal studies, graft recipients immunized prior to grafting have a fast and stronger immune rejection, (shows memory+specificity = 2 cardinal features of the immune response)
Term
can the ability to reject a graft be transferred to a naive individual? how?
Definition
yes, immunized animal T cells can be put in a non-immunized animal, who when grafted, will reject the transplant faster. this tells us the T cells, and thus immune system are involved. this can be double checked by administering drugs that lower T cell numbers and when this is done, graft rejection eases up
Term
what role do antibodies play in the different kinds of graft rejections? how do they cause injury?
Definition
antibodies are the major mechanism in hyperacute graft rejection and they play a role in acute+chronic graft rejection. antibodies cause injury by complement-dependent cytotoxicity, inflammation, and antibody-dependent cytotoxicity
Term
what role do T cells play in graft rejection?
Definition
T cell mediated reactions are the major mechanism in acute and chronic graft rejection
Term
when does hyperacute graft rejection occur? how does it happen?
Definition
hyperacute rejection occurs when there are preexisting antibodies in the recipient against donor antigens. when this happens, • antibodies fix complement, bring inflammatory cells and basically completely occlude the vasculature - so fast the pt will not get off the operating table.
Term
when does acute graft rejection occur? what are characteristics of its occurence?
Definition
acute graft rejection occurs when T cells become allo-reactive in days to months after the graft. it is marked by parenchymal cell damage, interstitial inflammation and endothelitis
Term
when does chronic graft rejection occur? what are characteristics of its occurence? what is thought to kick-start it?
Definition
chronic graft rejection is mediated mostly by T cells, thought some antibodies are involved, and occurs months to years after grafting. it is classified as chronic delayed type hypersensitivity and hallmarks include initmal, smooth muscle, cell proliferation and some occlusion. (there is some overlap in pathology between acute+chronic b/c it is basically a continuum). this kind of rejection is thought to be related to organ injury, could be related to nepho-toxic immunosuppressive agents or cytomegalovirus
Term
what are we talking about with chronic graft rejection which is a kind of delayed type hypersensitivity?
Definition
CD4s, macrophages, CD8s
Term
what is hyperacute graft rejection characterized by? when does it happen? what does it look like?
Definition
hyperacute graft rejection is characterized by rapid vascular occulusion, occurring within minutes after host blood vessels are anastomosed to graft vessels. the kidney turns purple, and fills up with thrombi and bloody urine. it is marked by intravascular clotting and thrombosis formation, the kidney is cynaotic, flaccid, mottled and non functional
Term
who does hyperacute graft rejection occur to?
Definition
people w/multiple transfusions, prior grafts, pregnancy - every baby's father is an allograft to the mother - specifically women who have had babies with more than one father.
Term
once a hyperacute rejection starts, can it be stopped?
Definition
no
Term
what is the mechanism for hyperacute graft rejection?
Definition
it is mediated by preexisting antibodies to vascular epithelium, leading to endothelial cell injury, complement activation, neutrophil accumulation and high levels of thrombi formation - necrosis occurs quickly
Term
are MHC class I or II involved in hyperacute graft rejection? are blood group antigens involved?
Definition
MHC I is always expressed on all cells so it is involved, MHC II can be involved because class II expression can be induced on endothelial cells in situations of trauma, inflammation, and infection. blood group (ABO) antigens can be involved.
Term
what kind of hypersensitivity reaction is a hyperacute graft rejection?
Definition
hyperacute graft rejections are type II hypersensitivity reactions because the antibodies are associated with something specific
Term
since both acute and chronic infections are mediated by T cells reacting to foreign MHC, and this shouldn't happen (positive selection tells us that T-cell clones that do not recognize self MHC do not get positively selected and should die in the thymus), what are the 2 theories as to why it does?
Definition
indirect and direct allo-recognition
Term
how is indirect allo-recognition theororized to occur?
Definition
the allo-MHC is picked up from the transplant by an APC, processed and presented as a peptide by MHC class II, which if there is tissue damage will be picked up by macrophages/dendritic cells and presented to CD4. also cross presentation can happen, (if some leaks out of phagosomes, gets ubiquinated etc.) and then allo-MHC peptide is presented by class I. either way, a self MHC molecule presents a peptide from foreign MHC
Term
how is direct T cell allo-MHC recognition theororized to occur?
Definition
either the self-MHC limited T cell recognizes the allogenic MHC molecule b/c its structure resembles a self MHC-foreign peptide complex OR the self MHC-restricted T cell recognizes a structure formed by both the allo-MHC AND the bound peptide
Term
what is acute graft associated with? when can it occur?
Definition
necrosis of parenchymal cells, mild interstitial hemorrhage, infiltration of interstitium by lymphocytes (CD4,8) and monocytes, and damage to the vascular endothelium (endothelitis) which differentiates it from antibody-mediated vasculitis. it can start from days to years after transplant.
Term
what is seen on a microscopic level with acute graft rejection?
Definition
marked increase in (dark purple) mononuclear cells
Term
how do the T cells incur damage in acute graft rejection?
Definition
CD8 CTLs are going to be responding to class I MHC presenting processed allo-MHC and performing their cytolytic function. CD4s responding to class II will be calling in macrophages, which cause more tissue damage, and release more allo-MHC, potentiating the process to continue
Term
what kind of hypersensitivity reaction is acute graft rejection?
Definition
delayed type hypersensitivity
Term
what is a drug that acute graft rejection is very responsive to? (in the absence of acute humoral rejection)
Definition
cyclosporine
Term
can antibodies be involved with acute graft rejection?
Definition
yes, IgG can be produced against MHC or other antigens and cause necrotizing vasculitis via activation of complement or neutrorophilic infiltration (b/c complement can be chemotactic for inflammatory cells or inflammatory cells can be directly activated by antibodies)
Term
because acute graft rejection involves antibodies, what may be seen in its event?
Definition
deposition of Igs, complement & fibrin as well as thrombosis and extensive necrosis of renal parenchyma, (necrosis is releated to both antibody-mediated acute and hyperacute graft rejections)
Term
in acute graft rejection, how does it appear if vasculitis is less acute? what is driving this process if antibodies aren't involved?
Definition
if vasculitis is less acute, acute graft rejection may be characterized by marked thickening of the intima, proliferation of fibroblasts, myocytes and foamy macrophages; similar in appearance to atherosclerosis. this process is caused by cytokines, (some of which cause the growth of vascular smooth muscles)
Term
what is seen histologically with hyperacute graft rejection?
Definition
thrombi
Term
what is seen histologically with cellular acute graft rejection?
Definition
swollen endothelial cells and accumulation of mononuclear cells
Term
what is seen histologically with humoral acute graft rejection?
Definition
proliferation of vascular smooth muscle cells - starting to occlude the intima
Term
when does chronic rejection occur? why is it seen more recently? how chronic kidney rejection reflected in creatinine levels?
Definition
chronic rejection occurs months to years after transplant and it has been occuring more as immunosuppressive therapy techniques have been improving b/c it can happen even under immunosuppressive therapy. creatinine level rise for chronic rejections of kidney transplant is slow
Term
what is chronic graft rejection marked by? is necrosis or endothelitis seen? what do these characteristics lead up to?
Definition
thickening of the vessel wall, smooth muscle proliferation, narrowing of the lumina (both antibody-mediated), *dense obliterative tubular intimal fibrosis (chronic process), *tubular atrophy. necrosis or endothelitis is not seen. these changes lead up to ischemia and loss of function, (reason creatinine creeps up)
Term
what are the definitive markers for chronic graft rejection?
Definition
graft arteriosclerosis, tubular atrophy, interstitial fibrosis and smooth muscle proliferation
Term
what is "graft vs host disease" (GVH)? when does this happen?
Definition
when T cells from the graft attack the host antigens. this commonly happens with bone marrow transplants b/c it contains mature T-cells that can escape and recognize all host antigen as foreign
Term
what is acute GVH marked by? can it be fatal?
Definition
epithelial cell necrosis*, liver/skin/problems, skin rashes, jaundice, diarrhea - can be fatal
Term
what is chronic GVH marked by? can it be fatal?
Definition
fibrosis, skin atrophy, cholestatic jaundice (chronic liver disease), esophageal strictures (due to fibrosis/scarring), life-threatening infections (b/c host immune T cells carry MHC I+ sometimes II and are attacked by donor T cells). may be fatal.
Term
what is the difference between graft rejection and graft vs host disease?
Definition
graft rejection - host attacks donor tissue, GVH - donor attacks host
Term
when does graft vs host disease happen?
Definition
most frequently, GVH occurs with allogenic bone marrow grafts but it can happen following transplantation of any solid organ rich in lymphoid cells, (liver+unirradiated blood). b/c recipients are generally immunosuppressed, it makes it harder for their immune system to fight back
Term
what are the mechanisms of GVH?
Definition
donor T cells (particularly CD4+ TH1) present in the graft secrete cytokines and activate host macrophages, NK cells in a delayed hypersensitivity reaction. these T cells also still have the ability to expand clonally.
Term
what drug is the first line of treatment for graft rejection? what are its main indications? is it used with anything else?
Definition
cyclosporine, whose main indications are prevention of graft rejection as well as prevention of GVH. it can also be used in autoimmune disorders including some dermatologic ones. it is sometimes used with corticosteroids.
Term
what is the M/A for cyclosporine? does it affect other cytokines?
Definition
it blocks signaling intended to stimulate T cell IL-2 transcription by binding to cyclophilin. the cyclosporine/cyclophilin complex then blocks calcineurin activation, blocking dephosphorylation of NFAT. (other cytokines such as IFN-gamma and IL-3's effects are also similarly blocked)
Term
what are some common toxicities of cyclosporine?
Definition
nephrotoxicity (may actually contribute to chronic graft rejection), HTN, liver dysfunction, hirsutism, cholelithiasis, lymphomas (+other cancers - when you suppress the immune system malignancies in the immune system increase)
Term
what is the M/A of tacrolimus? what are its indications?
Definition
tacrolimus binds to FK-binding protein, and the subsequent complex blocks calcineurin, which then inhibits NFAT activation, blocking translation of IL-2. its indications are the same as cyclosporine (but it is not chemically similiar).
Term
what toxicities are associated with tacrolimus?
Definition
neurotoxicity*, hyperglycemia, HTN, hyperkalemia, GI complaints
Term
what are the effects of cyclosporine/tacrolimus on T lymphocytes?
Definition
reduced expression of IL-2,3,4, GM-CSF, and TNF-alpha. reduced cell division due to decreased IL-2, reduced Ca++ dependent exocytosis of cytotoxic granules. inhibition of antigen-driven apoptosis
Term
what are the effects of cyclosporine/tacrolimus on B lymphocytes?
Definition
inhibiton of cell division (due to lack of T-cell cytokines), inhibition of antigen-driven cell division, induction of apoptosis after B-cell activation (last two effects are unknown)
Term
what are the effects of cyclosporine/tacrolimus on granulocytes?
Definition
reduced Ca++ dependent exocytosis of granules
Term
what is the M/A of sirolimus? what does it block? what does it not block? when is it used/what is it used with?
Definition
sirolimus binds immunophilins, and inhibits calcineurin. sirolimus doesn't block cytokine/interleukin production BUT it does block T cells response to cytokines as well as B cell proliferation and Ig production. sirolimus also suppresses response to CSFs. it can be used with other immunosuppressives and its indications are similar to cyclosporine (graft rejections, GVH, skin conditions, auto-immune diseases).
Term
what are toxicities of sirolimus?
Definition
profound myelosuppression (particularly thrombocytopenia), hepatotoxicity, hypertriglyceridemia, diarrhea and headache
Term
what is the M/A of mycophenylate mofetil? what is the indication? what are common usages?
Definition
mycophenylate mofetil inhibits B & T proliferative responses in vitro via inhibition of de novo synthesis of purines (anti-mitotic). mycophenolate mofetil is indicated for prevention of graft rejection. it is commonly used in combination with prednisone (as alt to cyclosporine/tacrolimus) for refractory solid organ rejection, steroid refractory GVH, lupus nephritis, RA, and some dermatological disorderes
Term
what are toxicities of mycophenolate mofetil?
Definition
GI, diarrhea, vomiting, abdominal pain, myelosuppression (antiproliferative). any anti-mitotic will always cause GI problems b/c GI turns over often
Term
what is the M/A for glucocorticoids? how do they affect the lymph nodes/spleen? do they affect myeloid/erythroid production? whose cell cycle do they interfere with? what do they interfere with the production of? WBC chemotaxis? do they inhibit synthase? do they inhibit phagocytosis? do they inhibit any cytokines? do they affect cell or humoral mediated immunity? can they be used to treat graft rejection?
Definition
they reduce the size and (lymphoid) content of lymph nodes and spleen, but have no effect on proliferating myeloid and erythroid stem cells in bone marrow. they interfere with the cell cycle of activated lymphoid cells and inhibit production of inflammatory mediators (PAF - platelet aggregating factor, leukotriene, prostaglandins, histamine -> which is why they are used in acute inflammation often). they diminish chemotaxis and antimicrobial ability of monocytes/neutrophils, but they do not inhibit synthase or impair phagocytosis. they do affect IL-1 as well as IL-3,4,5,8 and TNF-alpa. they affect cell mediated responses more than humoral and used to treat graft rejection.
Term
what are indications for corticosteroids?
Definition
many, including skin rashes
Term
what are toxicities associated with corticosteroids?
Definition
osteoporosis w/long term pts, fluid-electrolyte disturbances (weight gain/fluid retention), thin fragile skin, impaired wound healing, some psychological effects (insomnia/psychosis) and endocrine effects including blood sugar raising
Term
what do anti-CD3 monoclonal antibodies do? when are they used?
Definition
deplete recipient T cells, they are used often in acute graft rejection
Term
what does CTLA4-IG do?
Definition
this is an activation induced homologue of CD 28/B7, so using this will inhibit T-cell activation by blocking co-stimulation
Term
what does the anti-CD40 ligand do?
Definition
blocks antibody production and T cell driven macrophage activation
Supporting users have an ad free experience!