immuno: transplants and tumors Flashcards
graft between identical twins (syngeneic, histocompatible)
graft rejection?
isograft
no graft rejection anticipated
allograft
btw same species
histoincompatible
rejection expected
alloreactive responses
IR against alloantigens (Ags that differ btw members of the same spp)
alloantibodies
Ab against alloantigens
graft btw diff species
xenograft
graft will be rejected
this transplant has a high success rate and no tissue typing due to immune privilege
corneal
allogenic BM/HSC transplant
bone marrow
peripheral blood
umbilical cord blood or placental blood
blood can be enriched for HSC pops by
hemapharesis or tx donor with CSFs (colony stim. factors)
CSFs (such as GM-CSF, IL-3) can enrich donor blood for
CD34+ HSC
the BM recipient is tx with
anti-mitotic drugs and irradiation (BM ablation) prior to donation
autologous HSC from BM
collect CD34+ HSC from BM–>cryopreserved–>ablative tx–>HSC thawed and infused
IR causes graft rejection: supporting evidence
2nd-set rejection happens faster
histo: lympho and mono infiltrate
athymic pts do not reject (need T cells)
slow rejection via IS dampening (lymphos, CMI)
hyperacute rejection
few hrs
preformed Abs to MHC, BG ags–>
activation of complement–>recruit. phagos, platelet activation–>thrombosis–>hemorrhage–>necrosis in transplant
fever, leukocytosis, loss of transplant function
CMI not involved
hyperacute rejection may be result of
ABO blood group incompatibility
Previous incompatible transplantations
Previous blood transfusions from a related donor
Pregnancy
acute rejection
begins few days-14 days complete
not prev. sensitized mostly, some 2nd set
infiltration lymphos, monos–>CTLs phagocytize and present transp. Ag to help T cell
reaction against MHC and mhc Ags
acute rejection may be prevented by
immsuppr tx: Abs against T lymphos: cortsters, other drugs
chronic rejection is a Type ???
Type 3 hypersensitivity
acute rejection is a Type ???
Type 4 hypersensitivity: CMI (Abs also)
chronic rejection
mos-yrs slowly lose function activation of CD4+ cells-->macro, CTL activation, Abs agains alloAgs (HLA class I), classical comp. pathway activation, ADCC
chronic rejection depends on…
imm. mechanisms that are active and cause histo changes
lymphoid prolif–>formation of follicles over time–>fibrotic changes (scarring)
immsuppr tx for chronic rejection
useless, damage already took place
Rituximab may slow down chronic rejection until other organ can be found
graft vs host reactions (GVH)
transplanted lymphocytes mount Type IV hypersn rxn against recipients tissues
(lymphos competent and host imm compromised)
occurs in BM transplant of with lymphos that “piggy back”
GVH s/s
rash, hepato-spenomegaly, lymphadenopathy, diarrhea, anemia, weight loss, wasting
leukemia pts that receive HSC transplant may have..
graft vs leukemia effect
donor T cells recognize minor histocompatibility/tumor sp. Ags–>donor cells attack/kill leukemia cells
major histocompatibility complex (MHC)
main influence on graft acceptance/rejection
-transplantation Ags
MHC is on…
gene products…
short arm of chromosome 6 HLA, closely linked genes: MHC class I: A, B, C MHC class II: DP, DQ, DR
HLA class I expressed on... vs HLA class II...
all nuc. cells
subset of hematopoeitic cells (dendritic) and thymocytes (but can be induced, as via IFN-y)
combo of the 6 MHC alleles makes up a
total number of HLA alleles expressed
haplotype
1 inherited from each parent- 2 total–>genotype
12 (6 loci x 2 haplotypes)
genetic polymorphism
multiple stable allelic forms of one gene in a population
-basis of forensics, paternity testing, DNA ancestry, tissue matching
??? initiate graft rejection without the requisite for processed peptide
HLA class II molecules
key initiating even in acute allograft rejection
direct activation of rec. CD4+ T cells by non self HLA class II on grafted tissue, or carried into recipient by “passenger leukocytes” in transplant
direct recognition
recog. of non self HLA (w/out processing foreign peptide)–>stimulus to recipient’s T cells
(unlike conventional IR)
up to 5% clones may respond (vs. 0.01-0.0001% if need TCR to bind self HLA class II and foreign peptide)
indirect recognition
recipient’s APC process donor Ag and present to T cells
chronic rejection
HLA class II: most potent transplantation Ag good paring btw donor and rec at ??? locus is assoc. with longest graft survival
HLA-DR
mechanisms activation
activation CD4+ T cells via recog of foreign HLA class II (+/- peptides) rec. CD8+ T cells directly activated by non self HLA class I but need CD4+T cell via *IL-2* production for full activation
important cytokines in graft rejection are mostly…
immune response is Type….
Th1
Type 1 IR
??? induces accumulation and activation of macros and inc. HLA class II expression macros may become cytolytic for transpl. cells
INF-y
??? increases HLA class I expression–>cytolysis of transplanted cells
INF-y, INF-a/B, TNF-a/B
??? is cytotoxic to graft cells
TNF-B
HLA matching of primary importance for..
kidney and BM allografts
less so for heart, liver
reason for rejection in HLA match
minor histocompatibility Ags
-not as rapid
while testing compatibility, ALWAYS do this first
Blood type
otherwise hyperacute rejection
genotype of HLA via
PCR and sequence analysis
sn, rapid, accurate
HLA sequence based typing
automated DNA seq. and computer analysis for HLA typing
sp. HLA genes:
exon 2 in Class II genes
exon 2, 3 in Class I genes
mixed lymphocyte reaction (MLR)
both donor and recipient cells combined, see if react
2-way: mixed in presence of H3-thymidine
if lymphos respond, cells will prolif and incorp. radioactive thymidine, + response
1-way: 1 is fixed, can’t prolif
either way, if +–>don’t do transplant
corticosteroids
inhibit gene expression (encoding cytokines/rec) in mult. cell types, down reg adhesion rec, inhibit phago and HLA mol. expression
often + antimetabolites
antimetabolites
(mitotic inhib, cytotoxic drugs) inhib lymph prolif, purine antags (azathioprine, mercaptopurine), DNA alkylating agents (chlorambucil, cyclophosphamide), methotraxate (folic acid antag that blocks purine biosyn)
(originally dev. to tx ca)
blocking agents
MoAbs against CD3 (block activation of both T cell types)
and against IL-2R (CD-25, IL-2 rec)
also against B7, CD28 (co-stim. molecules)
cyclosporine
fungal metabolite, anti-rejection
interferes w. gene transcription in T cells
(IL-2, IL-4, IFN-y, IL-2r)
effective prior transplantation, not during episode
FK 506 (Tacrolimus) and rapamycin
newer fungal metabolites, sim activity, diff structure to cylcosporine
total lymphoid irradiation
destroys many cell types, but also more radiation-sn T cells
goals of rejection prevention research
find agent that induces graft tolerance yet does not induce global immune suppression
main theory of ca immune: mutations in genes for neoplastic cells also lead to…
changes in expressed proteins
-should result in recog. of that protein as non self by immune system
evidence for IR to tumors
imm. suppr individuals have higher incidence tumor occurence/recurrence
newly transpl. tumors are rejected at high rate/more rapidly in animals prev. exposed to similar tumors (anamnestic IR, like 2nd set rejection)
imm. surveillance theory
lympho/mono infiltrates in solid tumors
immune surveillance theory: mech for allograft rejection evolved to protect against..
neoplasms, NK cells important
innate immunity
NK cells (via killer inhib. receptors) recog. lack of self HLA on tumor cells
large granular lymphos, capable of lysing virus-inf. cells/tumor cells w.out HLA + Ag recog.
no memory, occurs w.out precedent cell prolif
adaptive immunity
humoral immune response to tumors
cell mediated responses
tumor cells may be lysed by
IgG and IgM Ab and complement
-esp. singe tumor sells and metastases
less effective if tumor is large or encapsulated
tumor cells may be destroyed by ??? if opsonized by ???
phagos
IgG
Abs may neutralize spread of tumor cells by
sterically interfering with tumor cells’ ability to adhere to surrounding tissue and/or metastasize
ADCC
tumor Ags induce Abs(IgG) that bind tumor cell
K cell ( has Fc rec) attaches to tumor cell through Ab “bridge”
subst. released from K cells when close contact tumor cell–>apoptosis tumor cell (killing mech)
K cell can be..
NK*, CTL, eosin, macro, neutro, etc
CD8+ CTLs recognize tumor Ags thru
HLA class I molecules, then destroy tumor cell *single most important defense*
CTL is dependent on..
Th1 cytokines like IL-2
activated macros destroy tumor cells by rel.
lysosomal enzymes and TNF-a onto tumor cell surface
lymphokine-activated NK cells (LAK)
heterogenous, mostly NKs, lymphoid cells
from peripheral blood of ca pts (IL-2 presence) allows IR to escalate in vitro, transfused back w. IL-2
-not v. successful, toxic and $$
tumor-infiltrating lymphos (TIL)
NK, some T cells removed from tumors, Cx in presence of IL-2, transferred back with IL-2, low success
CD4+ T helper cells: do what??
produce cytokines that activate macros, induce CD8+ CTL activity, upreg HLA class I (on tumor cells), and HLA class II (APCs)
most imp. cytokine produced by CD4+ is ??? which acts by ???
IFN-y: attracts/activates macros to area of Ag and prev. emigration away upregulates HLA class I and II expression
production of ??? is key to activation of
CTL and NK cells
why IR not always effective at eliminating tumors: imm.priv. site
eye, brain, gonads, out layers of skin
“can hide”
why IR not always effective at eliminating tumors: anergy of infiltrating T cells due to …
lack of co-stim. molecules on tumor cells OR production of factors by tumor cell that inhibit T cell function
PGs and IL-10 (Th1 inhib. cytokine)
why IR not always effective at eliminating tumors: global imm. suppr
TGF-B: can inhib. Th1 response, dec. NK cell cytolytic activity, inhib. Ag uptake and presentation, dampen CD4+ and CD8+ function
why IR not always effective at eliminating tumors: dec. imm. recog due to ??
dampened HLA molecule expression on tumor cells
why IR not always effective at eliminating tumors: Ag modulation (“escape”)
tumors can alter Ag make-up regularly
-one that is least antigenic may survive IR
why IR not always effective at eliminating tumors: blocking factors
prevent recog of tumor cells as foreign, i.e. coating in polysacchs
- sec. Ags may “bind-up” Abs in circulation, prev. them from reaching Ags on tumor cell
- also “blocking Ab” may coat tumor cells preventing recog by CTL
why IR not always effective at eliminating tumors: size of tumor mass
ability of IS to destroy, remove tumor is INVERSELY proportional to size (harder to remove if larger)
-inaccessibility of imm. comps to interior
tumor immunotherapy
MoAbs sp. for surface molecules for initiating tumor cell killing via ADCC, opsonization and phagocytosis
Rituximab
anti-CD20
targets B cells in B cell lymphoma
Her2/neu protein
targets tumor cells in breast/ovarian ca
Certruximab
anti-EGFR
target ca cells in colorectal, head, neck ca
Tositumomab
anti-CD20 conj. to iodine 131 (toxic molecule)
tx non-Hodgkin’s lymphoma
tumor immunotherapy: vaccination
HPV to prev. cervical ca (6, 11, 16, 18)
GVH reaction sustained and increased severity via
MHC II induced expression: inc. number of cells expressing MHC II as well as inc. expression
T cell deficiency, B cell proliferation (more Lambda than Kappa), think…
leukemia, B cell lymphoma
B cell lymphoma common in HIV+..
dec. CD4+ T cells (leaders), loss of control
tx B cell lymphoma with..
Ritixumab (anti. CD20)
compl. activation, MAC activation–>tumor cell lysis
cerv/axillary LAD hyperCa, high LDH, inc. WBC counts, inc. atypical cells B cells, neutros, eosins WNL almost all CD4+ T cells, lack of CD8+ think...
T cell tumor
HTLV (if anti-HTLV IgG+)
if clonal, came from initiated cell
virus may “confound” antiviral Ag so can’t fight off tumor
tumor produced factors that can influence anti-tumor response
PGs
IL-10
TGF-B
(dec. T cell response)
Hep C
inc. liver enzymes, inc. a-FP–>
hepatocellular carcinoma
look for transplant: HLA genotyping (PCR) and seq., MLR (have time)
4 hrs
elev. liver enzymes, spiked fever, low complement
hyperacute rejection *did not do ABO* happens fast due to preformed AB complement being "used up" *no tx can save graft*
