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Flashcards in immuno: transplants and tumors Deck (91):
1

graft between identical twins (syngeneic, histocompatible)
graft rejection?

isograft
no graft rejection anticipated

2

allograft

btw same species
histoincompatible
rejection expected

3

alloreactive responses

IR against alloantigens (Ags that differ btw members of the same spp)

4

alloantibodies

Ab against alloantigens

5

graft btw diff species

xenograft
graft will be rejected

6

this transplant has a high success rate and no tissue typing due to immune privilege

corneal

7

allogenic BM/HSC transplant

bone marrow
peripheral blood
umbilical cord blood or placental blood

8

blood can be enriched for HSC pops by

hemapharesis or tx donor with CSFs (colony stim. factors)

9

CSFs (such as GM-CSF, IL-3) can enrich donor blood for

CD34+ HSC

10

the BM recipient is tx with

anti-mitotic drugs and irradiation (BM ablation) prior to donation

11

autologous HSC from BM

collect CD34+ HSC from BM-->cryopreserved-->ablative tx-->HSC thawed and infused

12

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)

13

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*

14

hyperacute rejection may be result of

ABO blood group incompatibility
Previous incompatible transplantations
Previous blood transfusions from a related donor
Pregnancy

15

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

16

acute rejection may be prevented by

immsuppr tx: Abs against T lymphos: cortsters, other drugs

17

chronic rejection is a Type ???

*Type 3 hypersensitivity*

18

acute rejection is a Type ???

*Type 4 hypersensitivity*: CMI (Abs also)

19

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

20

chronic rejection depends on...

imm. mechanisms that are active and cause histo changes
lymphoid prolif-->formation of follicles over time-->fibrotic changes (scarring)

21

immsuppr tx for chronic rejection

useless, damage already took place
*Rituximab* may slow down chronic rejection until other organ can be found

22

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"

23

GVH s/s

rash, hepato-spenomegaly, lymphadenopathy, diarrhea, anemia, weight loss, wasting

24

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

25

major histocompatibility complex (MHC)

main influence on graft acceptance/rejection
-transplantation Ags

26

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

27

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)

28

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)

29

genetic polymorphism

multiple stable allelic forms of one gene in a population
-basis of forensics, paternity testing, DNA ancestry, tissue matching

30

??? initiate graft rejection without the requisite for processed peptide

HLA class II molecules

31

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

32

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)

33

indirect recognition

recipient's APC process donor Ag and present to T cells
*chronic rejection*

34

HLA class II: most potent transplantation Ag
good paring btw donor and rec at ??? locus is assoc. with longest graft survival

HLA-DR

35

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

36

important cytokines in graft rejection are mostly...
immune response is Type....

Th1
Type 1 IR

37

??? induces accumulation and activation of macros and inc. HLA class II expression
macros may become cytolytic for transpl. cells

INF-y

38

??? increases HLA class I expression-->cytolysis of transplanted cells

INF-y, INF-a/B, TNF-a/B

39

??? is cytotoxic to graft cells

TNF-B

40

HLA matching of primary importance for..

kidney and BM allografts
less so for heart, liver

41

reason for rejection in HLA match

minor histocompatibility Ags
-not as rapid

42

while testing compatibility, ALWAYS do this first

Blood type
otherwise hyperacute rejection

43

genotype of HLA via

PCR and sequence analysis
sn, rapid, accurate

44

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

45

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*

46

corticosteroids

inhibit gene expression (encoding cytokines/rec) in mult. cell types, down reg adhesion rec, inhibit phago and HLA mol. expression
often + antimetabolites

47

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)

48

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)

49

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

50

FK 506 (Tacrolimus) and rapamycin

newer fungal metabolites, sim activity, diff structure to cylcosporine

51

total lymphoid irradiation

destroys many cell types, but also more radiation-sn T cells

52

goals of rejection prevention research

find agent that induces graft tolerance yet does not induce global immune suppression

53

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

54

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

55

immune surveillance theory: mech for allograft rejection evolved to protect against..

neoplasms, NK cells important

56

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*

57

adaptive immunity

humoral immune response to tumors
cell mediated responses

58

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

59

tumor cells may be destroyed by ??? if opsonized by ???

phagos
IgG

60

Abs may neutralize spread of tumor cells by

sterically interfering with tumor cells' ability to adhere to surrounding tissue and/or metastasize

61

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)

62

K cell can be..

NK*, CTL, eosin, macro, neutro, etc

63

CD8+ CTLs recognize tumor Ags thru

HLA class I molecules, then destroy tumor cell
*single most important defense*

64

CTL is dependent on..

Th1 cytokines like IL-2

65

activated macros destroy tumor cells by rel.

lysosomal enzymes and TNF-a onto tumor cell surface

66

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 $$

67

tumor-infiltrating lymphos (TIL)

NK, some T cells removed from tumors, Cx in presence of IL-2, transferred back with IL-2, low success

68

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)

69

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

70

production of ??? is key to activation of

CTL and NK cells

71

why IR not always effective at eliminating tumors: imm.priv. site

eye, brain, gonads, out layers of skin
"can hide"

72

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)*

73

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

74

why IR not always effective at eliminating tumors: dec. imm. recog due to ??

dampened HLA molecule expression on tumor cells

75

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

76

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

77

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

78

tumor immunotherapy

MoAbs sp. for surface molecules for initiating tumor cell killing via ADCC, opsonization and phagocytosis

79

Rituximab

anti-CD20
targets B cells in B cell lymphoma

80

Her2/neu protein

targets tumor cells in breast/ovarian ca

81

Certruximab

anti-EGFR
target ca cells in colorectal, head, neck ca

82

Tositumomab

anti-CD20 conj. to iodine 131 (toxic molecule)
tx non-Hodgkin's lymphoma

83

tumor immunotherapy: vaccination

HPV to prev. cervical ca (6, 11, 16, 18)

84

GVH reaction sustained and increased severity via

MHC II induced expression: inc. number of cells expressing MHC II as well as inc. expression

85

T cell deficiency, B cell proliferation (more Lambda than Kappa), think...

leukemia, *B cell lymphoma*

86

B cell lymphoma common in HIV+..

dec. CD4+ T cells (leaders), loss of control

87

tx B cell lymphoma with..

Ritixumab (anti. CD20)
compl. activation, MAC activation-->tumor cell lysis

88

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

89

tumor produced factors that can influence anti-tumor response

PGs
IL-10
TGF-B
(dec. T cell response)

90

Hep C
inc. liver enzymes, inc. a-FP-->

hepatocellular carcinoma
look for transplant: HLA genotyping (PCR) and seq., MLR (have time)

91

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*

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