transplantation immunology

Flashcard maker : Clarence Louder
what cells do class I and II MHC present antigen to?
class I presents antigen from endogenous cells to CD8, class II presents antigen from exogenous cells to CD4
what is MHC restriction?
peptide antigen is recognized by T cells in the context of class I or II MHC
where are class I and II MHC found?
class I is found on all cells, class II is limited to just professional APCs
how do the structures of class I and II MHC differ?
class I has an alpha chain and a beta2 macroglobin, while class II has an alpha and a beta chain with no beta2 macroglobin
how many antigens do MHCs have? which and how many are matched clinically?
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
what are the types of tissue grafts that can be done?
autograft, isograft, allograft and xenograft
what is an autograft? when is it done? where is the graft taken from? when can this kind of graft be lost?
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
what is an isograft? when does it happen?
transplant from an identical twin to another identical twin, (genetics should match)
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?
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.
what is a xenograft?
tissue grafts done inbetween species
what is the order of organ transplant ranked by highest number of grafts done? what is the 5-year survival rate
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)
what happens in the absence of immunosuppressive therapy with allo/xenografts?
graft rejection
what are the three kinds of graft rejection?
chronic (now see this the most), acute, hyperacute (shouldn’t see this)
what causes graft rejection? how is this proven?
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)
can the ability to reject a graft be transferred to a naive individual? how?
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
what role do antibodies play in the different kinds of graft rejections? how do they cause injury?
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
what role do T cells play in graft rejection?
T cell mediated reactions are the major mechanism in acute and chronic graft rejection
when does hyperacute graft rejection occur? how does it happen?
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.
when does acute graft rejection occur? what are characteristics of its occurence?
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
when does chronic graft rejection occur? what are characteristics of its occurence? what is thought to kick-start it?
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
what are we talking about with chronic graft rejection which is a kind of delayed type hypersensitivity?
CD4s, macrophages, CD8s
what is hyperacute graft rejection characterized by? when does it happen? what does it look like?
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
who does hyperacute graft rejection occur to?
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.
once a hyperacute rejection starts, can it be stopped?
what is the mechanism for hyperacute graft rejection?
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
are MHC class I or II involved in hyperacute graft rejection? are blood group antigens involved?
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.
what kind of hypersensitivity reaction is a hyperacute graft rejection?
hyperacute graft rejections are type II hypersensitivity reactions because the antibodies are associated with something specific
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?
indirect and direct allo-recognition
how is indirect allo-recognition theororized to occur?
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
how is direct T cell allo-MHC recognition theororized to occur?
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
what is acute graft associated with? when can it occur?
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.
what is seen on a microscopic level with acute graft rejection?
marked increase in (dark purple) mononuclear cells
how do the T cells incur damage in acute graft rejection?
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
what kind of hypersensitivity reaction is acute graft rejection?
delayed type hypersensitivity
what is a drug that acute graft rejection is very responsive to? (in the absence of acute humoral rejection)
can antibodies be involved with acute graft rejection?
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)
because acute graft rejection involves antibodies, what may be seen in its event?
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)
in acute graft rejection, how does it appear if vasculitis is less acute? what is driving this process if antibodies aren’t involved?
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)
what is seen histologically with hyperacute graft rejection?
what is seen histologically with cellular acute graft rejection?
swollen endothelial cells and accumulation of mononuclear cells
what is seen histologically with humoral acute graft rejection?
proliferation of vascular smooth muscle cells – starting to occlude the intima
when does chronic rejection occur? why is it seen more recently? how chronic kidney rejection reflected in creatinine levels?
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
what is chronic graft rejection marked by? is necrosis or endothelitis seen? what do these characteristics lead up to?
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)
what are the definitive markers for chronic graft rejection?
graft arteriosclerosis, tubular atrophy, interstitial fibrosis and smooth muscle proliferation
what is “graft vs host disease” (GVH)? when does this happen?
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
what is acute GVH marked by? can it be fatal?
epithelial cell necrosis*, liver/skin/problems, skin rashes, jaundice, diarrhea – can be fatal
what is chronic GVH marked by? can it be fatal?
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.
what is the difference between graft rejection and graft vs host disease?
graft rejection – host attacks donor tissue, GVH – donor attacks host
when does graft vs host disease happen?
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
what are the mechanisms of GVH?
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.
what drug is the first line of treatment for graft rejection? what are its main indications? is it used with anything else?
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.
what is the M/A for cyclosporine? does it affect other cytokines?
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)
what are some common toxicities of cyclosporine?
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)
what is the M/A of tacrolimus? what are its indications?
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).
what toxicities are associated with tacrolimus?
neurotoxicity*, hyperglycemia, HTN, hyperkalemia, GI complaints
what are the effects of cyclosporine/tacrolimus on T lymphocytes?
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
what are the effects of cyclosporine/tacrolimus on B lymphocytes?
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)
what are the effects of cyclosporine/tacrolimus on granulocytes?
reduced Ca++ dependent exocytosis of granules
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?
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).
what are toxicities of sirolimus?
profound myelosuppression (particularly thrombocytopenia), hepatotoxicity, hypertriglyceridemia, diarrhea and headache
what is the M/A of mycophenylate mofetil? what is the indication? what are common usages?
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
what are toxicities of mycophenolate mofetil?
GI, diarrhea, vomiting, abdominal pain, myelosuppression (antiproliferative). any anti-mitotic will always cause GI problems b/c GI turns over often
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?
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.
what are indications for corticosteroids?
many, including skin rashes
what are toxicities associated with corticosteroids?
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
what do anti-CD3 monoclonal antibodies do? when are they used?
deplete recipient T cells, they are used often in acute graft rejection
what does CTLA4-IG do?
this is an activation induced homologue of CD 28/B7, so using this will inhibit T-cell activation by blocking co-stimulation
what does the anti-CD40 ligand do?
blocks antibody production and T cell driven macrophage activation

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