Imunologi Transplantasi Modul Ai
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Transcript of Imunologi Transplantasi Modul Ai
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IMUNOLOGI TRANSPLANTASI
monica
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Imunologi Transplantasi
• Rangkaian kejadian yg muncul pada saat dilakukannya transplantasi.
• Hambatan terbesar.
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TRANSPLANTASI
• PEMINDAHAN ORGAN ATAU JARINGAN DARI DONOR KE RESIPIEN / HOST
• MACAM :– ISOGRAFT– AUTOGRAFT– ALLOGRAFT– XENOGRAFT
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Reaksi PenolakanKomponen sistem imun yang terlibat :
1) Antigen presenting cells – • Dendritic cells• Macrophages• Activated B Cells
2) B cells and antibodies – • Preformed antibodies• Natural antibodies• Preformed antibodies from prior sensatization• Induced antibodies
3) T cells4) Other cells –
• Natural killer cells• T cells that express NK cell – associated Markers• Monocytes/Macrophages
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Reaksi Penolakan
– MINOR H ANTIGEN CD8 T CELL• POLIMORFISME• TEREKSPRESI PD SEMUA SEL• ANTIBODY• PEPTIDE YG DIKENALI SELF MHC• TIDAK TERDETEKSI
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Imunologi Transplantasi Allogenik• MHC :
– Penentu self / foreign– Gen polimorfik– Diwariskan dari kedua orang tua– Terekspresi scr ko-dominan
• Alloantigens menimbulkan respon imun selular dan humoral.
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Pengenalan Alloantigens
• Direct / LangsungPengenalan molekul MHC utuh yg dipresentasikan oleh APC donor pada graft– Prinsip : molekul MHC self mengenali struktur molekul MHC alogenik
yg utuh– Limfosit T CD8+ and CD4+
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Figure 5-1. T cell recognition of a peptide-MHC complex
Downloaded from: StudentConsult (on 29 March 2010 03:41 AM)
© 2005 Elsevier
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Indirect / Tidak Langsung
MHC donor diproses dan dipresentasikan oleh APC
resipien
Prinsip : molekul MHC donor diproses spt antigen asing
lainnya
Sel T CD4+ saja
Molekul MHC klas II
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Aktivasi Sel T Aloreaktif dan Reaksi Penolakan Allograft
• APC donor migrasi ke nodus limfatikus regional Sel TH resipien
• Sel TH alloreaktif menginduksi munculnya sel TDTH dan CTL migrasi ke graft rejection
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Aktivasi Sel T Aloreaktif dan Reaksi Penolakan Allograft
( )SENSATIZATIONPassenger leukocyte
.Class II MHCantigen
2IL HT HT
HTHT
Donar kidney
CTLDTHTCTL
DTHT
LYMPH NODEEFFECTOR
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Peran CD4+ and CD8+ T Cells
• CD4+ berdeferensiasi sel efektor yg memproduksi sitokin– Merusak graft dng reaksi spt DTH
• CD8+ – Direct menghancurkan sel berinti graft
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Peran Sitokin pada Graft Rejection
• IL – 2, IFN – , dan TNF - mediator penting pada graft rejection.
• IL – α induksi proliferasi dan munculnya sel T• IFN - sitokin utama pada respon DTH• TNF - efek sitotoksik direct pada sel graft• Induksi ekspresi molekul MHC klas I dan II pada sel graft• The interferon (α, dan ), TNF – α dan TNF -
meningkatkan ekspresi MHC klas I• IFN - meningkatkan ekspresi MHC klas II
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Mekanisme Efektor pada Reaksi Penolakan
• HOST VERSUS GRAFT REJECTION
• GRAFT VERSUS HOST REJECTION
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HOST VERSUS GRAFT REJECTION
– TERGANTUNG KETIDAKCOCOKAN ANTIGEN– MHC YG TERUTAMA– MINOR ANTIGEN– MEMORI– TERDIRI DARI :
• Hyperacute Rejection• Acute Rejection• Chronic Rejection
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HYPERACUTE REJECTION
– TERJADI SEGERA (MENIT)– ANTIBODI YG PERNAH TERBENTUK VS
ANTIGEN DONOR ENDOTEL– ENDOTEL VASKULAR AKTIFKAN
KOMPLEMEN– ORGAN KEKURANGAN OKSIGEN– PENGANGKATAN GRAFT
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Hyperacute Rejection
1. Preformed Ab, 2. complement activation, 3. neutrophil margination, 4. inflammation, 5. Thrombosis formation
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Acute Rejection
• Injuri vaskular dan parenkim• Dimediasi oleh sel T dan antibodi• Minggu I transplantasi jika terapi imunosupresi tidak
ada• PASSENGER LEUKOCYTE APC (MHC +
COSTIMULATORY MOLECULE) DONOR• Direct• CTL
• Insiden tinggi (30%) untuk 90 hzri pertama
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Acute Rejection
1. T-cell, macrophage and Ab mediated,2. myocyte and endothelial damage, 3. Inflammation
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Chronic Rejection
• Terjadi pada transplantasi organ yang paling solid : jantung, ginjal, paru, hati
• Karakterisasi : abnormalitas fibrosis dan vaskular + hilangkan fungsi graft pada jangka waktu yg lama
• ANTIGEN GRAFT• Indirect• TH1 (MAKROFAG)
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Chronic Rejection
1. Macrophage – T cell mediated2. Concentric medial hyperplasia3. Chronic DTH reaction
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GRAFT VS HOST REACTION
– IMUNOCOMPROMISED HOST VS IMMUNOKOMPETENT DONOR
– DIARE, ERITEMA, WEIGHT LOSS, DEMAM, DLL KEMATIAN
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Transfusi DarahTransfusi Darah
Transfuse Not transfused
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TRANSPLANTASI YG SUKSES
• MENCOCOKAN MOLEKUL MHC
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TRANSPLANTASI YG SUKSES
• HLA A, HLA B, HLA DR• HLA DR PALING POLIMORFIK
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Setiap HLA terdiri dari berbagai macam protein yg spesifik (HLA A1, HLA B 5, dst )
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• HLA diturunkan secara Haplotipe
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BASIC RULE PENURUNAN HLA• 25 % mendapat HLA yang sama (2
haplotipe yg sama)• 25 % tidak mendapat HLA yang sama
(tidak ada haplotipe yg sama)• 50 % mendapat sharing 1 haplotipe
dengan saudara lain• Kesimpulan : setiap orang memiliki
kemungkinan identical match dengan saudara sebesar 1 : 4
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TRANSPLANTASI YG SUKSES
• MENCOCOKAN MHC– SEROLOGICAL ASSAY
• MENGETAHUI ALEL HLA• ANTIBODI VS ALEL HLA DONOR & HOST
– MIXED LEUKOCYTE REACTION• PEMBELAHAN CD4 & CD8 T CELL
TERHADAP MHC CLASS II & CLASS I YG ASING
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KESULITAN
HLA TYPING : SURVIVAL TP TDK CEGAH RX PENOLAKAN
• ANTIBODI TIDAK DPT MENDETEKSI SEMUA ALEL MHC
• MINOR HISTOCOMPATIBLITY (MINOR H) ANTIGEN
• WAKTU TERBATAS (TRANSPLANTASI JANTUNG)
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OBAT IMUNOSUPRESAN
• KEGUNAAN :– ALERGI– AUTOIMUN– REAKSI PENOLAKAN TRANSPLANTASI
• UMUMNYA TIDAK ANTIGEN SPESIFIK & INFEKSI
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OBAT IMUNOSUPRESANMACAMNYA :• ANTI-INFLAMATORY AGENTS
– KORTIKOSTEROID (PREDNISON, DLL)• OBAT SITOTOKSIK BUNUH SEL EFEKTOR
– AZATHIOPRINE, CYCLOPHOSPHAMIDE• OBAT YG MEMBLOK AKTIVASI SEL T
– CYCLOSPORIN A, TACROLIMUS• ANTI LYMPHOCYTE GLOBULIN (ALG)• ANTIBODI MONOKLONAL
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XENOGRAFT
• MOLEKUL MHC SANGAT ASING• HYPERACUTE REJECTION• KH DAN ADHESION MOLECULE• TRANSGENIC ANIMAL
– CD46, CD55, CD59, DAF human complement-inhibitory molecule
– H-transferase ubah KH hewan menjadi KH manusia
• PENELITIAN LEBIH LANJUT
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PRIVILEGED IMMUNITY
• JANIN– SETENGAH ANTIGEN ASING TERHADAP IBU– PLASENTA : TEMPAT KONTAK JANIN DNG IBU– TROFOBLAS :
• TIDAK MENGEKSPRESI MHC I & II• MENGEKSPRESI HLA-G BLOK SEL NK (KIR)
• AVASKULER ORGAN : KORNEA
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Stem Cell Research
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DEFINISI• Sebuah sel yang mampu membelah dan
berdeferensiasi secara terus menerus
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MACAM SEL PUNCAStem cell
type Description Examples
Totipotent Each cell can develop into a new individual
Cells from early (1-3 days) embryos
Pluripotent Cells can form any (over 200) cell types
Some cells of blastocyst (5 to 14 days)
MultipotentCells differentiated, but can form a number of other tissues
Fetal tissue, cord blood, and adult stem cells
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Stadium Embriogenesis
Day 1Fertilized egg
Day 1Fertilized egg
Day 22-cell embryo
Day 22-cell embryo
Day 3-4Multi-cell embryo
Day 3-4Multi-cell embryo
Day 5-6BlastocystDay 5-6
BlastocystDay 11-14Tissue Differentiation
Day 11-14Tissue Differentiation
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TURUNAN DAN KEGUNAAN Embryonic Stem Cell Lines
Isolate inner cell mass(destroys embryo)
Isolate inner cell mass(destroys embryo)
Heart muscleKidney
Liver
“Special sauce”(largely unknown)
Day 5-6BlastocystDay 5-6
Blastocyst
Inner cells(forms fetus)Inner cells
(forms fetus)
Outer cells(forms placenta)
Outer cells(forms placenta)
Heartrepaired
Culture cellsCulture cells
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PENGGUNAAN TEKNOLOGI SEL PUNCA
• Replaceable tissues/organs• Repair of defective cell types• Delivery of genetic therapies• Delivery chemotherapeutic agents
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TRANSPLANTASI SEL PUNCA
• PLURIPOTEN• SUMBER :
– SUMSUM TULANG– DARAH (+G-CSF)– TALI PUSAT
• PREPARASI RESIPIEN / HOST– OBAT SITOTOKSIK– MEMBUAT RUANG UNTUK STEM CELL
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TRANPLANTASI STEM CELL
• AKIBAT : GRAFT VS HOST DISEASE (GVHD)• CARA MENGATASI :
– MARKER SEL T MATURE SUMSUM TULANG DONOR
– PAKAI TALI PUSAT :• BANYAK STEM CELL• SEDIKIT SEL T MATURE
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KETIDAKPASTIAN DLM PENELITIAN SEL PUNCA
• Apakah ESC manusia in vitro dpt berdeferensiasi menjadi semua jenis sel manusia dewasa ?
• Apakah sel punca yg dikultur in vitro akan berfungsi spt sel yg berkembang pd embrio ?
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TANTANGAN PENELITIAN SEL PUNCA
• Sel punca perlu berdeferensiasi menjadi sel yg tepat sebelum digunakan.
• Abnormalitas jumlah dan struktur kromosom ditemukan dalam kultur ESC.
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• Perkembangan dan proliferasi Sel punca HARUS dikontrol begitu ditranplantasikan ke host (pasien).
• Kemungkinan penolakan transplantasi sel punca masih tinggi.
TANTANGAN PENELITIAN SEL PUNCA
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TANTANGAN PENELITIAN SEL PUNCA
• Kontaminasi oleh virus, bakteri, jamur, dan Mycoplasma.
• Penggunaan sel “feeder” tikus untuk menumbuhkan ESC dpt menimbulkan masalah yg berkaitan dengan xenotransplantation.
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KESIMPULAN
• SEL PUNCA MERUPAKAN ALTERNATIF TERAPI YG MENJANJIKAN
• PENGGUNAANNYA HARUS HATI-HATI KARENA MSH BANYAK HAL YG BELUM DIKETAHUI