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