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
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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
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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