This document contains information about the Department of Urology at the Government Royapettah Hospital and Kilpauk Medical College in Chennai, India. It lists the professors and assistant professors in the department. It then provides a historical overview of the key discoveries in transplantation immunology from the early 1900s to the 1980s that helped identify the genetic factors underlying transplant rejection. It discusses the major histocompatibility complex and its role in the immune response to transplanted organs.
ABO Incompatible Kidney Transplantation, Michael Casey, MD (W-0007)UF Nephrology
Welcome to the Division of Nephrology, Hypertension, & Renal Transplantation within the Department of Medicine at the University of Florida. The University of Florida is an exciting academic community filled with people passionate in their academic pursuit. The Division of Nephrology, Hypertension, & Renal Transplantation is distinguished by the impact, breadth, and depth of its clinical, training, and research programs. It is the Highest ranked Division of Nephrology within Florida, 13th top program nationally, and is comprised of distinguished faculty, all of whom are involved in patient care, research and education. Our research interests include cutting edge research and collaborations with Departments throughout the University.
For CME Credit, visit our website to register and complete the necessary requirements.
http://nephrology.medicine.ufl.edu
ABO Incompatible Kidney Transplantation, Michael Casey, MD (W-0007)UF Nephrology
Welcome to the Division of Nephrology, Hypertension, & Renal Transplantation within the Department of Medicine at the University of Florida. The University of Florida is an exciting academic community filled with people passionate in their academic pursuit. The Division of Nephrology, Hypertension, & Renal Transplantation is distinguished by the impact, breadth, and depth of its clinical, training, and research programs. It is the Highest ranked Division of Nephrology within Florida, 13th top program nationally, and is comprised of distinguished faculty, all of whom are involved in patient care, research and education. Our research interests include cutting edge research and collaborations with Departments throughout the University.
For CME Credit, visit our website to register and complete the necessary requirements.
http://nephrology.medicine.ufl.edu
introduction, history, classification of grafts, transplantation antigens, role of MHC in transplantation, immunology of allogenic transplantation, types of graft rejection, immunology of xenogeneic transplatation, organ trannsplantation.
Question 1 200-300 words..cite sourcesChoose one of the five im.docxIRESH3
Question 1: 200-300 words..cite sources
Choose one of the five immunoglobulin isotypes and discuss biological properties related to your selected isotype. What clinical effects would you expect if your body no longer produced this isotype? How could these effects be mediated?
Paper
Read the “Tools for Human Leukocyte Antigen Antibody Detection and Their Application to Transplanting Sensitized Patients” article in this week’s Electronic Reserve Readings.
Write a 450 to 700-word paper that includes the following:
Analyze the current challenges with organ transplantation related to the genetic variability of MHC.
Describe the challenges of human leukocyte antigen (HLA) matching and identifying sensitized individuals.
Format your paper consistent with APA guidelines. Use at least 3 to 5 different references in your paper.
Transplantation
Issue: Volume 86(3), 15 August 2008, pp 384-390
Copyright: (C) 2008 Lippincott Williams & Wilkins, Inc.
Publication Type: [Editorials and Perspectives: Overview]
DOI: 10.1097/TP.0b013e31817c90f5
ISSN: 0041-1337
Accession: 00007890-200808150-00003
Keywords: Renal transplantation, HLA antibody detection, Sensitized
patients
[Editorials and Perspectives: Overview]
Tools for Human Leukocyte Antigen Antibody Detection and Their Application to
Transplanting Sensitized Patients
Fuggle, Susan V.1,2,3,5; Martin, Susan4
Author Information
1 Transplant Immunology and Immunogenetics, Oxford Transplant Centre, Churchill
Hospital, Oxford, United Kingdom.
2 Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom.
3 UK Transplant, Bristol, United Kingdom.
4 Transplantation Laboratory, Manchester Royal Infirmary, Manchester, United
Kingdom.
5 Address correspondence to: Susan V. Fuggle, Ph.D., Transplant Immunology and
Immunogenetics, Oxford Transplant Centre, Churchill Hospital, Oxford OX3 7LJ,
United Kingdom.
E-mail: [email protected]
Received 8 January 2008. Revision requested 11 February 2008.
Accepted 14 April 2008.
----------------------------------------------
Outline
Abstract
Antibody Identification
Complement Dependent Cytotoxicity
Flow Cytometry
Solid Phase Assays
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Luminex
Patient Sensitization Profile
Transplanting Sensitized Patients
ACKNOWLEDGMENTS
REFERENCES
Abstract
In recent years there have been major advances in the technology for the
detection and definition of human leukocyte antigen antibodies. In this overview
we describe the evolution in laboratory technology, the techniques currently
available and consider their application in antibody specificity definition and
in understanding a patient's sensitization profile. We discuss the importance of
antibody specificity definition in facilitating efficient national organ
allocation and informi ...
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
2. Professors:
Prof. Dr. G. Sivasankar, M.S., M.Ch.,
Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
Dr. J. Sivabalan, M.S., M.Ch.,
Dr. R. Bhargavi, M.S., M.Ch.,
Dr. S. Raju, M.S., M.Ch.,
Dr. K. Muthurathinam, M.S., M.Ch.,
Dr. D. Tamilselvan, M.S., M.Ch.,
Dr. K. Senthilkumar, M.S., M.Ch.
Dept Of Urology, KMC and GRH, Chennai 2
3. C.C. LITTLE & ERNEST TYYZER
1914
Genetic basis for transplantation
rejection
“Tumors transplanted between
genetically identical mice grew
normally, but tumors transplanted
between non-identical mice were
rejected and failed to grow”
Dept Of Urology, KMC and GRH, Chennai 3
4. PETER MEDAWAR
Role of the immune system in transplant reject
“Skin graft transplants in world war two victims
showed that skin transplants between
individuals had much higher rejection rates
then self-transplants within an individual”
“Suppressing the immune system delayed skin
transplant rejection”
1960 Nobel Prize
Dept Of Urology, KMC and GRH, Chennai 4
5. GEORGE SNELL (1930s) & PETER GORER
(1940s)
Individually isolated the genetic factors
that when similar allowed transplantation
between mouse strains
Naming them H and antigen II respectively
These factors were in fact one and the
same, and the locus was named H-2
Snell coined the term "histocompatibility“
Dept Of Urology, KMC and GRH, Chennai 5
6. JEAN DAUSSET (1950s)
Human version of the histocompatibility
complex
Snell, Dausset and Baruj Benacerraf -
1980 Nobel Prize
Dept Of Urology, KMC and GRH, Chennai 6
8. • Dendritic cells
• Macrophages
• Activated B Cells
Antigen presenting cells
B cells and antibodies
T cells
• Natural killer cells
• T cells that express NK cell – associated
Markers
• Monocytes/Macrophages
Other cells
Dept Of Urology, KMC and GRH, Chennai 8
10. Initial & most important barrier
Rejected immediately due to the presence of circulating preformed anti-A
and/or anti-B antibodies.
Transplantation across ABO disparate blood groups
ABO blood group B or O may receive a kidney from an ABO A2 donor if their
anti-A antibody titer is low (IgG ≤ 1:2)
A2 antigen - less reactive & expressed in lower amounts on the surface of red blood
cells and tissue cells
Dept Of Urology, KMC and GRH, Chennai 10
12. Anti-A/B antibodies are aimed to be below a certain threshold (less than
1:32) at the time of ABOi kidney transplantation and during the first 2 weeks
after surgery.
Thereafter, even a rebound of anti-A/B antibodies does not appear to harm
the kidney transplant, a phenomenon that is called accommodation
Dept Of Urology, KMC and GRH, Chennai 12
15. Cell surface glycoproteins
Function as peptide display molecules
Enable the immune system to distinguish between ‘self’ and ‘non-self’
Dept Of Urology, KMC and GRH, Chennai 15
16. Gene complex encoding Major Histocompatibility
complex proteins in humans
Chromosome 6p21.31
3.6 Mbp complex – over 200 genes
Regulates immune system
Highly polymorphic
Dept Of Urology, KMC and GRH, Chennai 16
18. Consist of a heavy chain with three domains
(alpha1, alpha2, alpha3) and an invariable
light chain called beta-2 microglobulin
Alpha3 domain anchors the molecule into
the cell, while the alpha1 and alpha2
domains form a peptide binding groove.
Beta 2-microglobulin, 12kDa, non-MHC
encoded, non-transmembrane, non covalently
bound to alpha chain
Alpha3 - Highly Conserved Among MHC I
Molecules; Interacts with CD8+ TCyt cell
Dept Of Urology, KMC and GRH, Chennai 18
19. • Class I MHC is found in almost all
nucleated cell.
• Presents endogenous antigen.
• The formed cleft can bind peptides of 8 -10
amino acids in a flexible extended
conformation.
• CD8 + T cell are responsive
Dept Of Urology, KMC and GRH, Chennai 19
22. • Alpha-chain of 34kDa
• Beta-chain of 29kDa
• NO beta-2 microglobulin
• Peptide antigen in a groove formed from
alpha1 & beta1 chains
Dept Of Urology, KMC and GRH, Chennai 22
23. Expressed on antigen presenting cells
(mononuclear phagocytes, B lymphocytes,
dendriticcells) as well as some endothelial
cells and thymus epithelium.
Expressed on the endothelial cells of
glomeruli and peritubular capillaries
Presents exogenous antigen.
CD4+ T cells are responsive
Dept Of Urology, KMC and GRH, Chennai 23
27. Probability that a sibling has inherited the same two haplotypes as a brother
or sister - 25 %
Probability that he/she inherited either one – 50%
Probability that he/she inherited neither - 25 %
Dept Of Urology, KMC and GRH, Chennai 27
29. Direct Presentation
• MHC molecule displayed by antigen-presenting cells
(APCs) in the graft is recognized by recipient T cells
without a need for host APCs.
Indirect Presentation
• Donor MHC molecules are captured and processed
by recipient APCs and then presented to T cells
Dept Of Urology, KMC and GRH, Chennai 29
32. Alloreactive CD4+ and CD8+ T cells that are activated by graft alloantigens
cause rejection by distinct mechanisms.
CD4+ helper T cells - differentiate into cytokine producing effector cells
damage grafts by cytokine mediated inflammation (similar to a
delayed-type hypersensitivity (DTH) reaction)
CD8+ T cells - differentiate into cytotoxic T lymphocytes (CTLs) kills
nucleated cells in the graft that express the allogeneic class I MHC
molecules.
CTLs also secrete inflammatory cytokines, which can contribute to graft
damage.
Dept Of Urology, KMC and GRH, Chennai 32
33. Most high-affinity alloantibodies are produced by helper T cell–dependent
activation of alloreactive B cells
The antigens most frequently recognized by alloantibodies in graft rejection
are donor HLA molecules, including both class I and class II MHC proteins.
Dept Of Urology, KMC and GRH, Chennai 33
34. Anti-HLA antibodies do not occur naturally (as do anti-ABO antibodies)
There are three ways that an individual can be exposed to HLA antigens and
subsequently develop anti-HLA antibodies
Blood product transfusions
Pregnancy
Tissue transplantation
Donor specific antibodies (DSAs), if present in high amounts, will
cause immediate (hyperacute) graft loss and if present in small
amounts will limit the survival of an allograft.
Dept Of Urology, KMC and GRH, Chennai 34
35. Donor harvest
Anastomosis of donor & recipient vessels
Recipient immune response to transplanted organ
Dept Of Urology, KMC and GRH, Chennai 35
36. Donor harvest
Anastomosis of donor & recipient vessels
Recipient immune response to transplanted organ
Dept Of Urology, KMC and GRH, Chennai 36
37. Donor kidney – resident immune cells such as dendritic cells
Resident dendritic cells – dormant
Acquire phagocytic ability and mobility upon slightest injury to kidney
Events activating resident dendritic cells:
Low blood flow to the kidney
Anoxia
Deceased donor – rapid swings in blood pressure (early ht follow by hypotens
phase) due to catecholamine induced autonomic storm
Brain death massive cytokine storm
“Donor kidney is highly activated even before removal”
Dept Of Urology, KMC and GRH, Chennai 37
38. Ischemia / Anoxia induced death of donor kidney cells
Ischemic cells spill intracellular contents
Contains immunologically active molecule – “DAMAGE
ACTIVATED MOLECULAR PATTERNS” (DAMPs)
Receptors for DAMPs – in epithelial, mesenchymal &
endothelial cells within donor kidney (TLRs / NLRs)
Receptor ligand complex sets off biochemical signalling
pathway induce inflammatory signals & cell death
pathways
DAMP/TLR/NLR interactions strong attractants for
recipient inflammatory cells
Dept Of Urology, KMC and GRH, Chennai 38
40. GREATER THE ISCHEMIC DAMAGE
MORE THE DAMP/TLR/NLR SIGNALING
MORE THE INFLAMMATORY CELLS PRESENTATION TO RECIPIENT
GREATER THE ACTIVATION OF RECIPIENT’S IMMUNE SYSTEM
Dept Of Urology, KMC and GRH, Chennai 40
41. Donor harvest
Anastomosis of donor & recipient vessels
Recipient immune response to transplanted organ
Dept Of Urology, KMC and GRH, Chennai 41
42. Recipient exposed to torrent of DAMPs/cytokines /
chemokines
Recipient immune cells vigorously infiltrate donor
tissue
Augements ischemia induced tissue injury
Activated donor dendritic cells migrate to T cell rich
regions of recipient’s lymph nodes
Donor dendritic cells – Recipient T cell interaction
key initiating event of cellular rejection
T cells discriminate between ‘self’ and ‘nonself’ based
on the foreigness of HLA / peptide complex presented
Dept Of Urology, KMC and GRH, Chennai 42
43. Donor harvest
Anastomosis of donor & recipient vessels
Recipient immune response to transplanted organ
Dept Of Urology, KMC and GRH, Chennai 43
44. Dendritic cell HLA / peptide complex with T-cell receptor several cell surface molecules
coalesce at the junction between the two cell types “IMMUNOLOGICAL SYNAPSE”
Immunological synapse – juxtaposed Tcell / T cell receptor / Dendritic cell (HLA/peptide) /
costimulatory / adhesion molecules
Provides the go signal to T cell
Immunological synapse – needs to be formed in order for the T cell to receive proper
combination of activation signals
Dept Of Urology, KMC and GRH, Chennai 44
45. IMMUNOLOGICAL SYNAPSE FORMATION
BIOCHEMICAL SIGNALLING TURNED ON
Activation of calcineurin
Activation of mitogen activated protein kinases
Genes transcribed secretion of cytokines (IL2)
Dept Of Urology, KMC and GRH, Chennai 45
46. Regulates gene transcription, cell division, cell survival, cell death
IL2 – IL2 R on surface of T cells activates three different cytoplasmic
signalling cascades (block receptor interaction – daclizumab, basiliximab)
Mitogen activated protein
(MAP) kinase pathway
Phosphoinositide 3 kinase
(PI3K) pathway
Janus kinase/signal
transducers and activators
of transcription protein
pathway (JAK/STAT)
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47. Remains activated as long as the synapse exists
The cells stays in contact for a longer period of time if a greater disparity
exists between HLA molecules of donor & recipient
Drugs aimed at disrupting this contact
Belatacept – CTLA4 Ig fusion protein
Alefacept – anti CD2 antibody
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50. ABO and Rh blood typing
Cross matching (Preformed
antibodies)
HLA typing
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51. Serological typing
Molecular typing
Important : HLA A, B, DR
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52. HLA TYPING
HLA typing of the donor kidney and
Recipient : expressed as “1-0-0-mismatch”
that corresponds to the pair of alleles
mismatched, respectively, at HLA-A, HLA-B
and HLA-DR.
These three antigens are the considered as
the most important ones in kidney
transplantation.
Influence of HLA-DR mismatching had the
most effect during the first six months post-
transplant while the maximal effect of HLA-B
mismatching occurred two years post-
transplant
HLA-A mismatches have a deleterious effect
on long-term graft survival
Dept Of Urology, KMC and GRH, Chennai 52
53. ADCC – Antibody dependent cell mediated cytotoxicity
CDC – Complement dependent cytotoxicity
Dept Of Urology, KMC and GRH, Chennai 53
54. A tray containing sera with antibodies to a multitude of known HLA alleles is
used
Recipient lymphocytes are introduced into the tray wells contacting sera,
complement and dye.
In tray wells where antibodies can bind to the antigens on the surface of
lymphocytes; complement is activated. This results in complement pathways
triggered resulting in cell death, ultimately allowing the dye to enter the cell.
Tray wells with significant cell death are then identified under phase contrast
microscopy.
Through a process of comparison and elimination of positive wells the HLA
type is assigned.
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56. The key benefit of serologic typing is that results are available in a short
period.
This is particularly important in deceased donor renal transplantation
LIMITATION: Lack of sera with antibody specificities that are capable of
identifying the ever-growing number of HLA alleles
More advanced methods of typing currently available & serological typing has
fallen into disuse
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57. Degree of cytotoxicity expressed as %PRA
% of lymphocytes in the cell panel which has undergone lysis as a result of
complement action
20% - minimum cut off for positive result
Dept Of Urology, KMC and GRH, Chennai 57
58. DNA-based HLA typing methods using molecular techniques
1. Sequence specific oligonucleotide probe hybridization(SSOP)
2. Sequence-specific primer amplification (SSP)
3. Sequencing-based typing (SBT)
4. Reference strand-based conformation analysis (RSCA)
5. Nextgeneration sequencing (NGS)
6. Short tandem repeat (STR) genotyping
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59. In this approach extracted DNA from the subject is amplified in several wells.
Each well has primers that are complementary to specific HLA alleles.
In wells where DNA probes are complementary to the specific sequence of the HLA
molecule, an amplification product is formed.
This is then instilled into an agarose gel and undergoes electrophoresis where they
appear as a band.
HLA typing is then allocated by matching the primers of the amplification product
to DNA sequences
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60. Amplified DNA is mixed with oligonucleotide probes that are complementary to
specific segments of the DNA of different alleles.
Unique HLA alleles are then identified using fluorescent tags.
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61. The usual route for sensitisation
towards HLA antigens occurs in
three instances
• Pregnancy
• Post blood transfusion
• Prior transplantation
METHODS FOR HLA ANTIBODY
SCREENING
• Cytotoxic cell based
• Solid phase antibody screening –
employs soluble or recombinant
HLA molecules instead of
lymphocytes
• ELISA
• Microbead platform / single
antigen beads
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62. Recipient serum + Donor lymphocytes in
individual wells along with complement &
dye
Serum with Ab + Donor lymphocyte
complement activation cell death
uptake of dye
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64. Limitations: detects only complement binding antibodies
False positive: non HLA antibodies, Autoantibodies & nonspecific IgM
antibodies
False negative: low antibody titre ( as high levels are required for
complement mediated action)
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65. Antibody levels vary with time due to new antigen exposures and
immunological sensitisation
Recently drawn recipient serum with donor lymphocytes – best
Positive T & B cell cross match Ab against Class I & II
Positive B cell cross match Ab against Type II antigens alone or low levels
of Ab to type I
Positive T cell cross match technical error
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66. Positive T cell cross match
• Poor outcome &
unacceptably high incidence
of acute graft rejection
• Desensitisation persistent
positive cross match
ABSOLUTE
CONTRAINDICATION
Positive B cell cross match
• Not as consistently
associated with humoral
rejection as positive T cell
cross matches
• Less significance in acute/
hyperacute rejection
• Still warrant desensitization
prior to transplant
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67. Donor lymphocytes + recipient’s serum
binds to donor specific antibodies
Quantified by detectors in impedence flow
cytometer
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68. Measurement of
fluorescence intensity
as a ratio of the
control
Serial dilution of
serum & minimum
dilution which yields
negative result gives a
measurable estimate
Dept Of Urology, KMC and GRH, Chennai 68
69. Interpretation : negative CDC + Positive flow cytometry
Non- complement fixing antibodies
Non HLA antibodies
Low level of anitbodies
CDC negative + Positive T cell flow cytometry significantly poorer absolute
5 year graft survival rates than those who were both negative
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70. Recipient serum + Purified HLA molecules +
Enzyme conjugated
Uses HLA glycoprotein immobilized into microtitre
wells
Recipient’s serum is added
Specific antibodies bind to the epitopes available
Wash anti IgG with a passenger reporter
molecule (alkaline phosphatase) is added which
combines with anti HLA antibody
Wash to remove unbound antibody
Substrate is added which after dephosphorylation
by reporter color change
Dept Of Urology, KMC and GRH, Chennai 70
71. Beads labelled with fluorescein – impregnated with
different ratios of two flurochromes resulting in a signal
unique to specific bead
Each bead have one or more HLA molecule incorporated
Incubation of recipient serum with beads
Washed and incubated with a second antibody
(antihuman IgGantibody) labelled with phycoerthyrin
Two lasers are used to excite the fluorochorme of bead
and the phyoerythrin bound to Ab
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72. Multiple synthetic microspheres with single given HLA antigen coating incubated with
recipient serum and recipient’s panel reactive antibodies are identified by Luminex
flow analyser
Based on the comparison of anti HLA antibodies of the recipient to donor HLA
antigens
E.g. Recipient’s PRA – MFI >10,000 : A2, A68, B57, DR1, DQ2
Donor HLA – A1, B57, C35, DP2, DQ23, DR 7
Predicts eventual cross match
Assist in rapid identification of suitable donor
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73. Allorecognition is the first step of a series of
complex events that leads to T-cell activation,
antibody production, and allograft rejection
Matching of donor and recipient for MHC antigens
and for preformed HLA antibodies has been shown
to have a significant positive effect on graft
acceptance
Knowledge of the immune mechanisms is critical in
developing strategies to minimize rejection and in
developing new drugs and treatments that blunt
the effects of the immune system on transplanted
organs, thereby ensuring longer survival of these
organs
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