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Transplant Immunology WHY TRANSPLANT TISSUES OR ORGANS? Replace dysfunctional/nonfunctional tissue or organs ------------------------------------------------------------------------------ High technology medicine Specialized healthcare professionals Specialized facilities Specialized support Pathology Radiology - Life saving - Very Expensive ------------------------------------------------------------------------------ DEFINITIONS OF TYPES OF TRANSPLANTS: ---------------------------------------------------------------------Classification scheme: depends upon: - the species of donor and recipient - same or different? - genetic similarity of donor & recipient (assuming both are form the same species) - identical versus - non-identical ---------------------------------------------------------------------- NOMENCLATURE: Donor (graft) & Recipient (host) IMPORTANT! Same Genetically Type of Species Identical transplant / tissue -----------------------------------------------------------------------------Self-> Self Yes Yes Autologous graft Autograft Twin A -> B* Yes Yes Isogeneic graft (syngeneic) Isograft (syngeneic graft) Person A --> B Yes No Allogeneic graft Allograft** Species A --> B No No Xenogeneic graft Xenograft -----------------------------------------------------------------------------* Also applies to individuals of an inbred strain (e.g., inbred mice) ** Most common type of transplant in humans IMPORTANT! WHAT ARE THE RULES OF TRANSPLANTATION? Type of Graft Graft fate without immunosuppression of the recipient (host) ---------------------------------------------------------Autograft Accepted Isograft Accepted Allograft Rejected* Xenograft Rejected* ---------------------------------------------------------* Graft (donor) and Host (recipient) are antigenically dissimilar Tissue Autograftt Twin “A” TWIN “B” Tissue Isograft (syngeneic graft) Tissue Allogeneic graft (allograft) Tissue Xenograft CLASSIFICATION BY GRAFT LOCATION Orthograft: transplanted organ is placed in the normal organ location (heart) Heterotopic: transplanted organ is placed in an unnatural location (kidney in pelvis) WHAT ARE THE TRANSPLANTATION ANTIGENS? IMPORTANT! Transplantation Relative Antigens Polymorphism -----------------------------------------------------------------------------1) ABO Limited 2) Major histocompatibility complex (MHC)* Very high 3) Minor histocompatibility antigens(non-MHC antigens) Limited 4) Xenoantigens Extremely high -----------------------------------------------------------------------------* Human MHC = HLA Complex, class I and class II MHC HOW DOES THE RECIPIENT RECOGNIZE THE DONOR AS FOREIGN? --------------------------------------------------------------------------H o s t (Recipient) TCR and B cell receptors recognize d o n o r (graft) antigens as f o r e i g n --------------------------------------------------------------------------- IMPORTANT CONCEPT: ------------------------------------------------------------------------------ the greater the difference in peptide sequences between graft and recipient - the stronger the immune response to the graft (donor) ------------------------------------------------------------------------------ HOW CAN FOREIGN CLASS II MHC PRESENT PEPTIDES TO HOST TCRs? Classification of the phases of tissue rejection Minutes- Hours Days Weeks Months Years Hyperacute Acute Subacute Chronic Pre-existing immunity to graft antigens Yes Antibody No CMI CMI Antibody + CMI Hyperacute Acute Subacute Chronic Minutes- Hours Days Weeks Months Years Type of Phase T ime Mechanism Donor - Recipient frame Mismatch -----------------------------------------------------------------------------Hyperacute Minutes -hours Pre-existing ABO antibodies MHC anti-ABO, anti-MHC Acute vascular obstruction (2 0 set rejection) ------------------------------------------------------------------------------ Type of Phase T ime Mechanism Donor - Recipient frame Mismatch -----------------------------------------------------------------------------Acute* Days Reactivation of sensitized T cells; 2 nd set rejection Class I or II MHC; minor histocompatibility -----------------------------------------------------------------------------* some sources refer to this as “accelerated ” Type of Phase T ime Mechanism Donor - Recipient frame Mismatch -----------------------------------------------------------------------------Subacute Days 10 activation Class II -weeks of T cells MHC “1 st set rejection” ------------------------------------------------------------------------------ Type of Phase T ime Mechanism Donor - Recipient frame Mismatch -----------------------------------------------------------------------------Chronic Months Cell-mediated Class I -Years and AbMHC, Minor mediated; histocompatiImmune bility complexes* -----------------------------------------------------------------------------* initial first set rejection evolves into a second set rejection TIME TO TISSUE REJECTION IN MICE -------------------------------------------------------------------------Skin graft in mice strain A --> Immune strain B response First set rejection 11 - 15 days Primary Second set rejection 6 - 8 days Secondary --------------------------------------------------------------------------- IMPORTANT First Kidney Transplant Surgery: 1950 Transplantation From Kidney to Stem cell History of Transplantation in Iran 1st kidney transplantation in 1967 in Shiraz Dr. Sanadi Zadeh 1985 2 transplantation teams were organized and started to work actively 274 kidney transplant in 2 years L.R.D L.U.R.D. cadaveric 1988 • L.U.R.D program organized and managed successfully • Number of transplant teams grow to < 20 • To the end of 2002 => 14888 kidney transplant • Today => 1500 kidney transplant/yr in Iran THE NUMBER OF RENAL TRANSPLANTS PERFORMED IN IRAN FROM 1984 - 2002 1800 1650 1600 1422 Number of Txs 1400 1681 1169 1200 1000 813 800 755 1184 1186 853 827 687 583 600 453 400 200 500 245 98 6 158 18 0 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000 2001 2002 SOURCES OF KIDNEY DONATION IN IRAN ; 1984 - 2002 LURD 79% (N=11 292) LRD 19.2% (N=2746) CAD 1.8% (N=250) PATIENT AND GRAFT SURVIVAL RATE IN LIVING RELATED (LRD) AND LIVING UNRELATED (LURD) RENAL TRANSPLANTATION In Hashemi Nejad Hospital , Tehran 100 90 80 70 60 % 50 40 30 20 10 0 Patient survival P<0.05 Graft survival LRD (N=469) LURD (N=881) 1 2 3 4 5 6 Years Post Transplant 7 8 9 10 GRAFT SURVIVAL RATES IN HLA IDENTICAL, ONE HLA HAPLOTYPE MATCH AND LIVING UNRELATED RENAL TRANSPLANT In Hashemi Nejad Hospital , Tehran 100 90 80 70 60 50 % 40 30 20 10 0 P<0.001 P=0.35 HLA Identical (n=141) One HLA Haplo (n=307) Living Unrelated (n=881) 1 2 3 4 5 6 7 Years Post Transplant 8 9 10 Other Organ transplants Bone Marrow, Liver & Heart 1991 1ST BMT in Shariati Hospital (Dr. Ghavamzadeh et al 1991-2006 Total of 1468 BMT Allogenic 1044 Autologous 324 New Topics Human Stem cell Repertoire What are stem cells? • A stem cell is a cell whose job in the body is not yet determined • Every single cell in the body stems from this type of cell • Stem cells wait for signals to tell them what to become • Until it receives a signal, it must wait patiently and divide slowly • When it receives a signal, begin to differentiate • The signals tell stem cell to turn on certain cell type it supposed to become • These Super cell have a magic clinical potential in tissue repair • They represent the future relief of a wide range of incurable diseases • They could replace defective organ and tissues • They can restore the function of dysfunctional or non functional organs Where do they come from? Early embryonic stages Some Fetal tissues The Umbilical Cord Several Adult organs –Bone Marrow –Peripheral blood –Fat tissues –Etc… Adult stem cell? • Every single organ has it’s own stem cell • Bone Marrow • Heamatopoietic stem cell (HSC) • Endothelial stem cell (ESC) • Mesenchymal stem cell (MSC) Mesenchymal Stem Cells (MSCs) • MSCs are adult stem cells from BM that can differentiate into multiple nonhematopoietic cell lineages. • They can differentiate into osteoblast, adipocytes, chondrocytes, myocytes, cardiomyocytes, astrocytes, oligodenrocytes and neurons. • They have potential to down regulate and inhibit immune response in both recognition and elimination phases • Possible clinical application proposed for MSC include: • stem cell transplantation • Stem cell strategies for the repair of damaged organ and gene therapy • MSCs due to their immunomodulatory potential theoretically, they can be used allogenically The role of Mesenchymal Stem Cells in relationship with injured somatic tissue and non-immune cells CAN STEM CELLS BE ISOLATED AND USED? If so under what conditions and restrictions? The low frequency of MSC in bone marrow necessitate the in vitro expansion prior to clinical use • We evaluated the effect of long term culture on the senescence of these cells • Surprisingly , MSC loses their characteristic after several passages Therefore: It is much better to consider them for therapy early on BM MSC culture (passage 6) The goal of our stem cell therapy studies • Assessing the safeness of the stem cell injection • The patients improvement from a clinical point of view • The degree of damaged tissue repair Mesenchymal Stem Cell therapy for Multiple Sclerosis and Heart Diseases Results of MS treatment • 10 MS patients with secondary progressive disease has been transplanted • One patient improved 2.5 score in EDSS (expanded disability status scale) • 4 others showed some degree of improvement • 5 patients after MSCT has not hastened disease progress Results of MSCT in Heart disease Cardiac functional parameters of mean 18 month fallow up in test group Parameters Base line± SD After MSC ± SD P value NYHA LVEF SPECT 2.75 ± 0.70 38.75 ± 13 11 ± 2 1.38 ± 0.51 48.75± 6.4 7.75 ± 1.1 .000 .005 .002 Cardiac functional parameters of mean 18 month fallow up in control group Parameters Base line ± SD After pro. ± SD P value NYHA LVEF 2.75 ± 0.70 41.88 ± 8.42 2.13 ± 0.35 42.50 ± 8.86 .049 NS SPECT 10.88 ±1.95 9.75 ± 1.58 .007 Comparison of cardiac function in two groups. Groups Test group NYHA LVEF before after before 2.75 1.38 38.75 41.88 Control group 2.75 P value NS 2.13 .005 NS SPECT after before after 48.75 11 7.75 42.50 10.88 NS NS 9.75 .013 Potential Tumorigenicity of these cells Finally • It seems, like all other issues, – We must first consider all potential results and possibilities – BEFORE ANY INTERVENTION • Because – NOTHING COMES TO US WITHOUT A DEGREE OF RISK