Transplantation Science
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Transcript Transplantation Science
Transplantation Science
Lars Wramner
MD, Ph.D.
Transplantation
Organs:
– Kidney, liver, heart, lung, pancreas
Tissues:
– Cornea, skin, bone, heart valves
Blood:
– Erythrocytes, trombocytes, plasma
Bone marrow:
Transplantation
Autotransplantation
– Within one individual
Isotransplantation
– Between genetically identical individuals
Allotransplantation
– Between individuals from the same species
Xenotransplantation
– Between different species
Transplantation antigens
Antigen: A molecule recognised as foreign
Blood group antigens
– The ABO-system
MHC: The Major Histocompatibility Complex
– Humans: HLA, Human Leukocyte Antigens
– Mouse: H2. Rats: RT1
– Enormous heterogeneity
Others
Specific -Nonspecific
Non -specific inflammatory mechanisms:
– Macrophages, dendritic cells.
– NK cells
– Granulocytes
– Complement
Antigen-specific immune response:
– T-lymphocytes: TH, TC.
– B-lymphocytes: Immunoglobulin, IG.
MHC
Location:
– On the surface of nucleated cells.
Function:
– Antigen presentation. A foreign molecule + the MHCmolecule = altered self => antigen.
– Transplantation. A foreign MHC-molecule = altered
self => transplantation antigen.
Inflammation:
– Upregulated
Immune activation
Antigen presentation.
Cell-to-cell adhesion.
Signalling molecules.
Cytokine gene polymorphism.
Cell activation.
Effector mechanisms.
Antigen presentation
Antigen presenting cells, APC.
– Macrophages, dendritic cells
Antigen presentation
– Direct: Donor-APC with donor-MHC.
– Indirect: Recipient-APC with donor-MHC.
Cell-to-cell adhesion
Close and stable adhesion:
– Antigen presentation.
– Facilitate signalling.
Adhesion molecules:
– IgSF (ICAM, VCAM, LFA-3)
– Integrins: 1,2,3, LFA-1
– Selectins: E,L,P-selectins
Signalling molecules
Co-stimulation
Cytokines:
– Interleukins, IL
– Interferons
– TNF
– TGF-
– Others
Regulation of the immune response
Cytokine gene polymorphism
SNP, single nucleotide polymorphism.
Promoter region.
Detected by PCR-technique.
Inter-individual variation in cytokine-
production or receptor activity.
Different clinical outcome.
Cell activation
Step 1: Antigen - cytokine
– Ca-dependent pathway
– Ca-independent pathway
Step 2: Cytokine - cell proliferation cycle
– RAFT 1
– G1 -> S phase
Purine synthesis
– DeNovo pathway
7-10 days.
Effector mechanisms
TC (CD-8): Killer cells, cytotoxic cells.
TH (CD-4): Helper cells, promote
inflammation.
B-lymphocytes: Antibody production,
Acute rejection
Cellular infiltration
Cytokine production
– Upregulation of MHC
Tissue destruction
– Cytotoxic T cells
– Complement activation by antibodies
Thrombosis
Fibrosis
Clinical signs of acute rejection
Kidney:
– Creatinine elevation
– Lack of creatinine decline
Liver:
– Abnormal liver values.
Thoracic organs
– Protocol biopsies.
Clinical classification of rejections:
- Chronological
Hyperacute:
– Preformed antibodies.
– Within minutes-hours.
Acute:
– Mainly cellular
– Within weeks, < 3 months.
Chronic:
– After years, slowly progressing.
Clinical classification of rejections:
- Sensitive to treatment
Steroid treatment:
– Sensitive.
– Resistant. Need for antibody treatment.
Outcome
– Return to baseline level
– Stable at an elevated level
– Progressive
Chronic rejection
Inflammation
Arteriosclerosis
– Intimal thickening
Fibrosis
Organ specific destruction's
– Glomerular sclerosis and tubular atrophy
– Vanishing bile ducts and cellular ballooning
– Brochiolitis obliterans
Tolerance
Absence of activation:
– Self tolerance!
– Foetal tolerance!
– Tumour tolerance?
– Transplantation tolerance?
Mechanisms:
– Anergy
– Clonal deletion
– Suppresser cells
Clinical results, kidney
Acute rejection:
– 50 %. Nearly always reversible.
– Increased risk of chronic rejection.
1-year results:
– 95 % patient survival.
– 85-90 % graft survival.
– Few infections, normal life.
Long term:
– 50 % graft survival, appr 15 years.
TNF-gene polymorphism and
graft survival
Val av främmande organ
Blodgruppstillhörighet.
– Undantag, A2 -> 0
Transplantationsantigen
– Enäggstvilling
– HLA-identiska syskon
– Övriga utan främmande HLA-antigen
– Med påvisbara främmande antigen, > 90 %
Immunosuppression
Historik
60-talet:
– Steroider (Prednisolon)
– Azathiprin (Imurel)
80-talet:
– Calcineurinhämning I: Cyclosporin (Sandimmun)
– Lymfocytantikroppar: Polyklonalt (ATG), monoklonalt (OKT-3)
90-talet:
– Calcineurinhämning II: FK506 (Prograf)
– Purinesynteshämning: MMF (Cellcept)
– TOR-hämning: Rapamycin (Rapamune), Everolimus (?)
– IL-2 receptor hämning: Monoklonal a-k (Simulect, Zenapax)
Steroider
Verkan: Hämmar arachidonsyre kaskaden,
antigenpresentation, cytokinproduction,
adhesionsmolekyler och MHC-II och cellinteraktioner.
Biverkan: Hypertoni, blodsockerhöjning, osteoporos, acne,
hudatrofi, hämmad sårläkning, ulcus och muskelatrofi.
Användning:
– Profylax: Snabbt sjunkande, lågdos.
– Rejektion: Högdos några dar.
Cytokinhämning I
Verkan:Synteshämning genom
calcineurinblockad.
– Cyclosporin, CyA: Sandimmun Neoral
– Tacrolimus, FK506: Prograf
Biverkan:
– Njurtoxicitet, hypertoni, hårväxt (CyA), tremor,
gingiva hyperplasi, atheroscleros?
Calcineurinhämning
Quic kTime oc h en
Foto - JPEG-dekompr imerar e
kräv s f ör att kunna se bilden.
Cytokinhämning II
Verkan: Il-2 receptorblockad. Monoklonal
antikropp, Simulect och Zenapax.
Biverkan: Immunhämning !?
Ges som injektion 2-5 gånger.
Immunhämning i 2-5 månader.
Cytokinhämning III
Verkan: Hämmar effekten av receptoraktivering genom
blockad av TOR.
– Rapamycin: Rapamune
– Everolimus: ?
Biverkan: Hyperlipidemi, lätt benmärgshämning,
ledbesvär, slemhinnesår, pneumonit.
Ej nephrotoxiskt.
Hämmar cellproliferation: Tumörer, blodkärlsendotel,
ospecifik inflammation !?
Leflunomid ??
TOR-hämning
Quic kTime oc h en
Foto - JPEG-dekompr imerar e
kräv s f ör att kunna se bilden.
Hämning av celldelning
Verkan: Hämmar celldelning, främst lymfocyter, genom
purinsyntes hämning.
– Azathioprine (Imurel)
– MMF (Cellcept). Mer selektivt för lymfocyter.
Biverkan: Buksmärtor och diarré, pancytopeni och
slemhinnebesvär.
Mizoribine ?
Brequinarsodium ?
Purinsynteshämning
QuickTime och en
Foto - JPEG-dekomprimerare
krävs f ör att kunna se bilden.
Antilymfocytantikroppar
Verkan: Något oklar. Förmodligen celldöd, lys, och redistribution. Ger
långvarig lymfopeni i perifert blod.
Biverkan:
– Kraftiga akut influensaliknande besvär.
– Ledvärk.
– Ökad infektionsrisk.
– Risk för lymfom, senare.
Användning:
– Induktion.
– Avstötning.
Preparat:
– Polyklonalt: ATG
– Monoklonalt: OKT-3
Klinisk immunhämning I.
Inga mätmetoder av immunologisk hämning.
– Läkemedelskoncentration.
– Leukocytnivåer.
Allmänna doseringar:
– Vetenskap, kliniska studier.
– Beprövad erfarenhet.
Minimera biverkningar.
Kostnadseffektivt
Klinisk immunhämning II
Kombinationsterapi:
– Trippel-, dubbel- eller monoterapi.
– Successiv dosreduktion.
Profylaktisk terapi.
– Induktion, högdos.
– Underhåll, lågdos.
Avstötningsterapi:
– Högdos steroider, 3-5 dar.
– Antilymfocytantikroppar