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Immunology Final

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Inhibit the expression of many cytokines
corticosteroids
Inhibit migration of monocytes and neutrophils into inflamed tissue
corticosteroids
corticosteroids increase number of circulating
neutrophils
corticosteroids decrease number of circulating
lymphocytes
Inhibitors of Early T-cell Activation
– Cyclosporine
– Tacrolimus
Inhibitor of Late T-cell Function
Sirolimus
Introduction in late 1970s
CSA
From soil fungus Tolypocladium inflatum
CSA
Formed the basis for current immunosuppression
CSA
CSA binds the protein
cyclophilin
Cyclophilin-CSA complex competitively inhibits
calcineurin
Calcineurin activity leads to
IL-2 gene transcription
are present on
almost all cell types in the body and thereby
can present Ag of intracellular origin to CD
8 cells for destruction
MHC class I molecules
are only on
specialized antigen presenting cells and
present Ag of extracellular origin to CD4
cells
MHC class II molecules
The MHC molecules contain a large
number of
genetic variants
different forms of a given gene
Allele
proteins coded by alleles
Allotypes
Encoded on chromosome six
HLA
combination of HLA alleles
found on a given chromosome 6
Haplotype
Found on
B-cells, APCs,
activated T-cells
MHC Class II
chance of sibling match (HLA)
1 in 4
HLA most important for
transplantation
HLA-A, -B, -DR
Differences in HLA antigens cause
immune
response against transplanted tissues
Recipient's immune system attacks and kills
cells of the graft
Solid organ transplant rejection
Mature T-cells in grafted bone marrow attack
recipient’s tissue
BMT rejection
Must be done prior to grafting
ABO typing
RBCs carry __ on surface
A, B, O antigens
universal donor of packed RBCs
Type O
universal acceptor of packed
RBCs
Type AB
found on the epithelial and endothelial cells lining the
blood vessels in the transplanted organ
ABO antigens (not only on RBCs)
ABO mismatch leads to
hyperacute rejection
Measure reactivity of recipient cells to
donor blood cell antigen
microlymphocytotoxicity assay
Determines if recipient has antibody to donor
HLA
HLA testing
HLA testing - Donor white cells mixed with
recipient serum
Causes of HLA antibody production
Transfusions
Prior Transplant
Pregnancy
Based on timing after transplant and
associated immune response
types of graft rejection
occurs when host has pre-formed Ab to donor RBCs
Type II Hypersensitivity Reaction
Can occur when host has Abs against HLA class I
Type II Hypersensitivity Reaction
Cross reactive with surface antigens on
endothelial cells
Type II Hypersensitivity Reaction
The reaction is irreversible⬦therefore MUST
be prevented
Hyperacute Graft Rejection
Antibody dependent cell-mediated
cytotoxicity(ADCC) against endothelial cell
Hyperacute Graft Rejection
Can cause thrombi formation within capillaries
and arterioles
Activation of clotting pathways assocaited with Hyperacute Graft Rejection
leads to ischemia and necrosis of
graft
Occlusion
how to manage hyperacute graft rejection
reduce capillary occlusion and restore
perfusion
how to prevent hyperacute graft rejection
Careful tissue screening and blood typing and minimize blood transfusions to decrease
sensitization of recipient to alloantigens
T of F: Most clinical transplants are performed
against some HLA class I and/or II
difference
T
T-cell mediated alloreactions cause
rejection
reaction that occurs within days and is preventable
Acute Graft Rejection
has a direct and indirect pathway
Acute Graft Rejection
prevention of acute graft rejection
Initiation of aggressive and prompt
immunosuppression
Management includes: Immunosuppression
Removal of Allograft
acute or chronic graft rejection
Slow onset—months/years post-transplant occurs with
Chronic Graft Rejection
Progressive narrowing of arterial lumens
leading to reduced blood flow to graft tissue occurs with
Chronic Graft Rejection
Mechanism not fully elucidated
– Likely involves Minor Histocompatibility
Antigens
Chronic Graft Rejection
If fibrosis occurs in chronic graft rejection, __
are unlikely to be effective
immunosuppressants
Seen w/ all BMT at varying degrees
GVHD
Risk dependent on source of BM
GVHD
Donor marrow “attacks” host tissue
GVHD
All allogeneic BMT suffer some level of
__ d/t histocompatibility matching of
only leukocytes
GVHD
Graft tissue recognizes host antigens as
foreign
GVHD
Effects mainly seen in GI tract, skin, and
liver
GVHD
Presentation includes:
- Fever
– Rashes
– Diarrhea
– Abnormal liver function tests
GVHD
PBPCs harvested from donor by __
and infused into recipient
leukophoresis
Transplantation of peripheral blood
progenitor cells (PBPCs) instead of BM
PSCT
Can increase PBPCs by giving to __ ↑ # circulating stem cells
granulocyte colony
stimulating factors +/- chemotherapy
T or F: Need for general anesthesia for donor in PSCT
F
Use limited by adverse effects
Immunosuppression
Mechanism of action for Azathioprine
Interference in synthesis and metabolism of
RNA
Mechanism of action for Mycophenolate mofetil
Interference in synthesis and metabolism of
RNA
Mechanism of action for Cyclosporine
Calcineurin Inhibition
Mechanism of action for Tacrolimus
Calcineurin Inhibition
Mechanism of action for Sirolimus
Calcineurin Inhibition
Basiliximab
Daclizumab
Interleukin-2 Receptor Antagonists (monoclonal Ab)
Drugs that interfere in synthesis and metabolism of
RNA also
Inhibit cell proliferation
Cause sequestration of T cells in BM
Corticosteroids
Inhibit macrophage migration and
phagocytosis
Corticosteroids
Decreased IL-1 secretion from macrophages by corticosteroids results in
Inhibition of CTL
Decreased IL-2 secretion from T cells by corticosteroids results in
Inhibition of CTL
Inhibit early proliferation of B cells
Corticosteroids
loading dose of coricosteroids given pre- or
intra-operatively
250-1000 mg
maintenance dose (pre-taper) of corticosteroids
1-2 mg/kg/day
dose of pred given for acute graft rejection
100-200 mg
dose of methylpred given for acute graft rejection
250-1000 mg x 2-4 days with rapid taper back to maintenance dose
over 3-5 days
Affected by diet
CSA absorption
T or F: Neoral is bio-equivalent to Sandimmune
F
Use of CSA and Tacrolimus
prevention of allograft rejection with no role in treatment
ADR's include: Renal dysfunction (acute or chronic)
Decreased GFR w/in days of initiation
May be cumulative w/ other nephrotoxic agents
Neurotoxicity
Hypertension
Hirsutism
GI
CSA
Binds to FK506 binding protein
Tacrolimus
Similar mechanism and effect to CsA, approved in __
Tacrolimus; Approved in 1994
poorly, erratically absorbed
CSA and Tacrolimus
Metabolized by CYP450 system leading to drug interactions
CSA and Tacrolimus
ADRs do not include hirsutism but do include infection
Tacrolimus
Can cause weight loss, anorexia
Tacrolimus
Neurotoxicity, gastrointestinal: greater with
tacrolimus
Hypertension, hypercholesterolemia, hirsutism, gingival hyperplasia: greater with
CSA
From soil fungus Streptomyces hygroscopicus
Sirolimus
Binds to FKBP-12 (same as tacrolimus)
Sirolimus
Different MOA than CsA/tacrolimus
Sirolimus
Little or no effect on IL-2 production
Sirolimus
Markedly suppresses IL-2 and IL-4 driven Tcell proliferation
Sirolimus
Also inhibits IL-6 supported proliferation of IFN-alpha and beta
Sirolimus
Metabolized by CYP3A4 > 90% excretion in feces (no renal dosage adjustment necessary)
Sirolimus
Toxicity increases  15 ng/ml
Not routinely monitored
Sirolimus
ADRs are usually dose-dependent
Sirolimus
Nephrotoxicity rarely a problem
Sirolimus
Hyperlipidemia **
Hyperglycemia
Leukopenia **
Thrombocytopenia **
Elevated liver function tests
Sirolimus
Purine analogue acts as prodrug of active 6-mercaptopurine
Azathioprine
Incorporated into cellular DNA inhibiting purine synthesis
Azathioprine
Most active in replicating cells
Azathioprine
Inhibits humoral and cellular immunity during the initial stages of lymphoid differentiation
Azathioprine
Affects innate immune function through reduced neutrophil production and macrophage function
Azathioprine
Use began in early 1960s but declining in recent years with advances in effective less toxic agents
Azathioprine
Used in prevention of rejection
Not effective in treatment of acute rejection
Azathioprine
Maintenance dose may need titration based on WBC (3500-6000 cells/mm)
Azathioprine
Use-limiting effects include bone marrow suppression
Azathioprine
Semi-synthetic agent derived from the fermentation of several penicillum species
Mycophenolate Mofetil
Rapidly metabolized to active form (mycophenolic acid)
Mycophenolate Mofetil
Inhibits purine biosynthesis specific to lymphocytes
Mycophenolate Mofetil
Leads to selective blockade of B and T proliferative responses
Mycophenolate Mofetil
Used for prevention and treatment of acute rejection ; dosage reduction required in renal failure
Mycophenolate Mofetil
Drug concentrations not routinely monitored
Available both orally and intravenously
Mycophenolate Mofetil
Generally well-tolerated
Gastrointestinal (gastritis, nausea, cramping)
Bone-marrow suppression (rare compared to AZA)
Mycophenolate Mofetil
Produced by injecting human spleen cells into a horse
Antilymphocyte globulin
Potency is mainly in the IgG antibody fraction
Antilymphocyte globulin
binds to surface antigens on host lymphocytes causing opsonization and removal by RES
(Direct, complement assisted lysing of lymphocytes)
Lymphocyte immune globulin
Given iv through central line over 1-8 hours
Lymphocyte immune globulin
Efficacy is monitored by measuring T cell count (90% reduction from baseline)
Lymphocyte immune globulin
Antibody response stimulated secondary to non-human source
Lymphocyte immune globulin
Serum sickness
Lymphocyte immune globulin
limitation: batch-to-batch variability in potency and purity
Lymphocyte immune globulin
Variable immunosuppressive efficacy among different preparations
Lymphocyte immune globulin
limitation: contamination with other globulins
Lymphocyte immune globulin
Allergic reactions due to derivation from animal sources
Lymphocyte immune globulin
Derived from rabbits
Can be given peripherally
Antithymocyte globulin
No test dose required
Antithymocyte globulin
Murine monoclonal Ab of the IgG2a isotype that binds and inactivates the CD3 receptor on mature T cells
OKT3
T cells are opsonized and removed from circulation via the RES (like Lymphocyte immune globulin)
OKT3
Blocks the ability of the cells to be stimulated by foreign antigens
OKT3
Inhibits the generation and function of cytotoxic T cells responsible for graft rejection
OKT3
Use: Rejection prophylaxis, rejection treatment, treatment of steroid resistant rejection
OKT3
Monitoring: Lymphocyte subset populations, anti-__ circulating antibody
OKT3
Primary exposure to OKT3 results in the development of anti-OKT3 Ab’s as early as
7-10 days into therapy
Mild-Severe flu-like syndrome Related to cytokine release secondary to T cell activation
OKT3
Reaction lessens as number of circulating T cells is decreased
OKT3
Give methylprednisolone iv in combination with APAP & antihistamine prior to first two doses of
OKT3
Higher incidence of viral infections and malignancy
OKT3
Bind and block the alpha subunit of the IL-2 receptor on the surface of activated T lymphocytes
IL-2 Receptor Antagonists
IL-2 mediated activation of lymphocytes is inhibited
IL-2 Receptor Antagonists
IL-2 Receptor Antagonists are
Monoclonal antibodies
Use: Prevention of Acute Rejection Episode
Added to traditional transplant regimens
IL-2 Receptor Antagonists
Adverse Events: comparable to placebo
No increased risk of infection compared to traditional therapy
IL-2 Receptor Antagonists
No known drug interactions
Not commonly associated with infusion related reactions
IL-2 Receptor Antagonists
of the IL-2 Receptor Antagonists __ has greater affinity for IL-2 receptor and is less expensive
Basiliximab
Increased reports of anaphylaxis following the second dose of
Basiliximab
Metabolized by Cytochrome P450 3A4 in gut and liver
CSA
Erythromycin
Metoclopramide
Grapefruit Juice
cause:
Increased CSA absorption
Phenytoin
Rifampin
Cholestyramine
cause:
Decreased CSA absorption
Diltiazem, nicardipine, verapamil have this effect on CSA
Decreased CSA absorption
Ketoconazole, itraconazole, fluconazole have this effect on CSA
Decreased CSA absorption
Erythromycin, clarithromycin have this effect on CSA
Decreased CSA absorption (Ery also increases absorption?)
Oral Contraceptives have this effect on CSA
Decreased CSA absorption
Tacrolimus have this effect on CSA
Decreased CSA absorption
Nafcillin
Phenytoin have this effect on CSA
Increased CSA metabolism
Phenoybarbital, carbamazepine have this effect on CSA
Increased CSA metabolism
Rifampin
Isoniazid have this effect on CSA
Increased CSA metabolism
Aminoglycosides
Amphotericin B have this effect on CSA
Increased Nephrotoxicity
NSAIDs
Tacrolimus have this effect on CSA
Increased Nephrotoxicity
Diltiazem, verapamil have this effect on CSA regarding nephrotoxicity
Decrease Nephrotoxicity (but don't give it just because)
ACE-Inhibitors - Concomitant tx may lead to increased leukopenia
Azathioprine
Allopurinol- Increases levels of
Azathioprine
Aminosalicylates (olsalazine, mesalamine) - increased myleosuppression
Azathioprine
Antacids - Decrease __ absorption
MMF
with AZA- Increases Bone marrow suppression
MMF
Dec OC efficacy
MMF
Inc MMF conc d/t inhibition of tubular secretion
Probenecid
Cholestyramine - MMF __ absroption and efficacy
Decreases
when given with MMF, increased levels of __ seen d/t competition for tubular secretion
Acyclovir/Ganciclovir
Triple-Drug Therapy for cadaveric and LRD mis-match
Steroid
Calcineurin Inhibitor
Anti-metabolite
Dual Therapy for LRD exact HLA match
Calcineurin Inhibitor + Steroid
Steroid Pulse Therapy is used for
acute rejection
Require higher level of immunosuppression;
Prophylaxis:
OKT3 x 14 days
pancreas transplant
Pancreas Rejection treatment
OKT3 + Steroid
No Correlation between HLA matching and graft survival
Liver transplant
Status _ – Critically ill on life-support
I
Status _ – Requires hospitalization
II
Status _ – End Stage liver disease managed at home
III
Status _ – Not yet eligible for transplantation
IV
Prophylaxis
Steroids + Calcineurin Inhibitor + AZA or MMF
Heart transplant
More susceptible to rejection
Large population of T lymphocytes and macrophages
Constant contact with external antigens
Lung transplant
Extensive vascular bed; leads to increased susceptibility to rejection
lung
Rejection prophylaxis for lung transplant
Triple-drug regimen
3 Drug Regimen (Most Common)
Calcineurin Inhibitor + Cell Proliferation Inhibitor + Steroid
Effectively prevents rejection in renal transplant
OKT3 Induction
Usually given to high risk patients
Black race
Retransplant
Pediatric
HLA mismatch
Prolonged cold ischemia time
OKT3 Induction
Primarily studied in renal transplant
sirolimus
Sirolimus + __ to reduce nephrotoxicity
MMF + steroids
Sirolimus + __ to reduce leukopenias
CSA or FK-506 + steroids
Demonstrated significant reductions in biopsy proven acute rejection at 6 months
IL-2 Receptor Antagonists
80% effectiveness in acute renal rejection
OKT3
Second line after steroids due to
ADRs
Cost
High efficacy of steroids
OKT3
May be first-line in African Americans
OKT3
Lower response rate to steroids
African Americans
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