immunology of transplantation with mhc
TRANSCRIPT
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IMMUNOLOGY OF TRANSPLANT
DR R SATHYAJITH
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HISTORY Sir Peter Medawar – Father
of Transplantation – Worked on graft rejection and acquired immune tolerance – In 1944 showed that skin allograft between two mice are rejected.
Mitchison Avrion – Rejection is due to development of CMI to the graft.
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HISTORY 1st successful Tx – 1906 - Cornea Joseph E Murray – 1954 – 1st kidney
transplant bw identical twins in boston. Dr. Thomas E Starzl – 1967 – 1st liver Tx. Christian Bernard – 1967 – 1st heart Tx. Dr. Donnall E Thomas – 1968 – 1st BM Tx. Schwartz Dameshek – 1959 – Showed 6-
mercaptopurine was immunosupressive.
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DEFINITION Implantation of “non-self” tissue into the
body The process of taking cells, tissues, or
organs called a graft (transplant), from one part of individual and placing them into another (usually different individual).
Donor: the individual who provides the graft.
Recipient or Host: the individual who receives the graft.
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TYPES
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TYPES
Homograft = Allograft = Allogenic Heterograft = Xenograft = Xenogenic Syngeneic = Isograft
Orthotopic – graft placed in their normal anatomic location.
Heterotopic – graft placed into a site other than their normal one. They are useful when orthotopic placement may be technically difficult.
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TYPES Stored or Fresh.
Living or Cadaveric donor.
Live grafts/Vital grafts - Kidney, Heart.
Non living - Bone, Artery.
Static or Structural grafts.
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TRANSPLANTATION Transplantation immunology - sequence of
events that occurs after an allograft or xenograft is removed from donor and then transplanted into a recipient.
A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue.
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OBSTACLES FOR SUCCESS Control of infection Genetic matching of donors with host. Administering agents to inhibit the
immune system
Antiseptic techniques & Abx HLA typing and Tissue matching Immunosuppressive agents
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IS ALLOGRAFT REJECTION IMMUNOLOGICAL?
Strain AStrain Bgraft
Graft rejected in 14 days
Strain C
Graft B rejected in 7 daysGraft C rejected in 14 days
Thus, allograft rejection meets two important properties of immune system - Specificity and Memory.
Strain AStrain Bgraft
Strain C Strain B
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MAJOR HISTOCOMPATIBILITY COMPLEX
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GENES OF MHC ORGANIZED IN 3 CLASSES
Class I MHC genes Glycoproteins expressed on all nucleated cells Major function to present processed Ags to TC
Class II MHC genes Glycoproteins expressed on Macrophages, B-
cells, DCs Major function to present processed Ags to TH
Class III MHC genes Products that include secreted proteins that
have immune functions. Ex. Complement system, inflammatory molecules
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CLASSES OF MHC Class I MHC Genes Found In Regions A,
B and C In Humans (K and D In Mice) Class II MHC Genes Found In Regions
DR, DP and DQ (IA and IE In Mice) Class I and Class II MHC Share Structural
FeaturesBoth involved in APC
Class III MHC Have No Structural Similarity To Class I and IIEx. TNF, heat shock proteins, complement
components
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POLYGENIC/ POLYMORPHIC
• MHC Products Are Highly Polymorphic– Vary considerably from person to person
• However, Crossover Rate Is Low– 0.5% crossover rate– Inherited as 2 sets (one from father, one from mother)– Haplotype refers to set from mother or father
• MHC Alleles Are Co-dominantly Expressed– Both mother and father alleles are expressed
• Inbred Mice Haplotypes Are Designated With Italic Superscript– Ex. H-2b
– Designation refers to entire set of H-2 alleles
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CLASS 1 MHC• Comprised of 2 molecules
– chain (45 kDa), transmembrane– 2-microglobulin (12 kDa)
– Non-covalently associated with each other• Association Of Chain and 2 Is Required For Surface
Expression• Chain Made Up Of 3 Domains (1, 2 and 3) • 2-microglobulin Similar To 3
• 1 And 2 Form Peptide Binding Cleft– Fits peptide of about 8-10 a/a long
• 3 Highly Conserved Among MHC I Molecules– Interacts with CD8 (TC) molecule
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CLASS II MHC• Comprised of and chains
– chain and chain associate non-covalently
• and chains made up of domains– 1 and 2 ( chain) – 1 and 2 ( chain)
• 1and 1 form antigen binding cleft• and heterodimer has been shown to
dimerize• CD4 molecule binds 2/2 domains
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CLASS I MHC
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CLASS I AND II SPECIFICITY
• Several hundred allelic variants have been identified in umans
• However, up to 6 MHC I And 12 MHC II molecules are expressed in an individual
• Enormous number of peptides needs to be presented using these MHC molecules
• To achieve this task MHC molecules are not very specific for peptides (Unlike TCR and BCR)
• Promiscuous Binding Occurs– A peptide can bind a number of MHC– An MHC molecule can bind numerous peptides
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CLASS I AND II DIVERSITY AND POLYMORPHISM
• MHC is one of the most polymorphic complexes known
• Alleles can differ up to 20 a/a• Class I alleles in humans: 1884 A, 2490
B, 1384 C• Class II alleles in humans: HLA-DR
1094 , 7 - total combo=8302• HLA DP (34, 155, 5270t) and HLA
DQ (47, 165, 7755t)
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INHERITANCE OF MHC LOCUS
M/N Q/R
M/Q M/R N/Q N/R 2% Genetic Recombination
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CLASS I MHC PEPTIDES
• Peptides presented thru MHC I are endogenous proteins
• As few as 100 peptide/MHC complex can activate TC
• Peptide features– size 8-10 a/a, preferably 9
• Peptides bind MHC due to presence of specific a/a found at the ends of peptide. Ex. Glycine @ Position 2
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CLASS II MHC PEPTIDES
• Peptides presented through MHC II are exogenous– Processed thru endocytic pathway
• Peptides are presented to TH
• Peptides are 13-18 a/a long• Binding is due to central 13 a/a• Longer peptides can still bind MHC II• MHC I peptides fit exactly, not the Case
with MHC II peptides
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MHC EXPRESSION• Expression is regulated by many cytokines
– IFN, IFN, IFN and TNF increase MHC expression
• Transcription factors that increase MHC gene expression– CIITA (Transactivator), RFX (Transactivator)
• Some viruses decrease MHC expression– CMV, HBV, Ad12
• Reduction of MHC may allow for immune system evasion
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IMMUNOLOGY OF TRANSPLANT REJECTION
Recognition of transplanted cells that are self or foreign is determined by polymorphic genes (MHC) that are inherited from both parents and are expressed co-dominantly.
Alloantigen elicit both cell-mediated and humoral immune responses.
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IMMUNOLOGY OF TRANSPLANT REJECTION
Components of the Immune system involved in graft Rejection :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 cells
4) Other cells – Natural killer cells T cells that express NK cell – associated Markers Monocytes/Macrophages
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GRAFT REJECTION
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RECOGNITION OF ALLOANTIGENS
Direct Presentation Recognition of an intact MHC molecule displayed
by donor APC in the graft Basically, self MHC molecule recognizes the
structure of an intact allogeneic MHC molecule Involves both CD8+ and CD4+ T cells.
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RECOGNITION OF ALLOANTIGENS
Indirect Presentation
Donor MHC is processed and presented by
recipient APC
Basically, donor MHC molecule is handled like
any other foreign antigen
Involve only CD4+ T cells.
Antigen presentation by class II MHC molecules
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ACTIVATION OF ALLOREACTIVE T CELLS
Donor APCs migrate to regional lymph nodes and are recognized by the recipient’s TH cells.
Alloreactive TH cells in the recipient induce generation of TDTH cell and CTLs then migrate into the graft and cause graft rejection.
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ROLE OF CD4+ AND CD8+ T CELLS
CD4+ differentiate into cytokine producing effector cellsDamage graft by reactions similar to
DTH
CD8+ cells activated by direct pathway kill nucleated cells in the graft
CD8+ cells activated by the indirect pathway are self MHC-restricted
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ROLE OF CYTOKINES IN GRAFT REJECTION
IL – 2, IFN – , and TNF - are important mediators of
graft rejection.
IL – α promotes T-cell proliferation and generation of T –
Lymphocytes.
IFN - is central to the development of DTH response.
TNF - has direct cytotoxic effect on the cells of graft.
A number of cytokines promote graft rejection by
inducing expression of class – I or class – II MHC
molecule on graft cell.
The interferon (α, and ), TNF – α and TNF - all
increases class – I MHC expression, and IFN - increases
class – II MHC expression as well
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MECHANISM OF GRAFT REJECTION
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CLINICAL PRESENTATION OF GRAFT REJECTION
Hyperacute rejection – Within few hours, d/t preformed Ab
Acute rejection – 6m to 1y, d/t activation of CD4/Cd8 cells, production of cytokines.
Chronic rejection – d/t HI & CMI, TGF-beta
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HYPERACUTE REJECTION
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HYPERACUTE REJECTION
No vascularisation – White/pale Pre-existing Ab’s d/t –1. Repeated transfusions2. Repeated pregnancies3. Previous grafts4. Blood group incompatibility Kidney graft most vulnerable Liver relatively resistant
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ACUTE REJECTION Mediated by T cells Massive infiltration by host
macrophages and lymphocytes TH cell activation & proliferation Activation of DTH response CD8 Tc mediated cytotoxicity CD4 mediated cytotoxicity Ab production ADCC by NK cells
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ACUTE GRAFT REJECTION
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CHRONIC REJECTION Increased survival in 1st year Chronic rejection not prevented. Both HI & CMI
Depends on - Genetic disparity at HLA bw donor &
recipient Effectiveness of immunosupressive
drug regimen
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CHRONIC REJECTION
Cardinal features – Thickening & blocking of BV dt
proliferation of sm cellsDeposition of Ag-Ab complex in
graftFormation of scar tissue &
fibrosis
Main culprit – TGF-beta
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CHRONIC REJECTION
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CHRONIC REJECTION
Increased risk in – Previous episodes of acute rejection Inadequate immunosupression Initial delay in graft function Old age or HTN in donor Diabetes, HTN or DLP in recipient Reperfusion injury to organ Post transplant infection with CMV
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TX FROM MALE TO FEMALE
Male tissues contain XY When male tissue with XY is grafted
to female (XX), as females don't contain Y gene, the grafts may not be accepted
However grafts done from female to male are accepted.
The Phenomenon of unilateral sex linked histocompatibility is known as EICHWALD SILMSER effect.
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PEARLS - SUCCESSFUL TRANSPLANTATION
Organ to be transplanted should be selected best with ABO compatibility and HLA matching
Immunosuppressant – Multiple drugs are used Intensive induction and low dose
maintenance
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PEARLS - SUCCESSFUL TRANSPLANTATION
Tx dysfunction monitoring & Rx of established rejection
Withdrawal or reduction of dose of a drug whenever toxicity outweighs the benefits
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HLA MATCHING Major Ag difference found on MHC
molecules Many different alleles of MHC
molecules If donor & recipient share as many
alleles as possible, the strength of rejection response is reduced
In humans, HLA matching is rarely perfect b/w unrelated donors
Loci outside MHC can also lead to rejection (MinorHC)
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HLA MATCHING
No attempt to match MinorHC Little possibility of getting a good
match (Even perfectly matched at MHC locus, will not be matched at MinorHC) Effect of matching is too small to be
clinically significant
Tx b/w HLA identical individuals require some degree of immune suppression.
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HLA TYPING HLA matching is most important for
kidney & BM Liver & heart Tx may survive with
greater mismatching
Matching/ Mismatching of class I Ag has a lesser effect on graft survival unless there is also mismatching of class II Ag
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HLA TYPING
Classically done using –
Micro-cytotoxicity (MCT)Mixed lymphocyte reaction (MLR)
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MICROCYTOTOXICITY WBC from potential donors and
recipient are added to separate wells of a microtitre plate
Single Ab directed against an Ag of interest is added to both well and incubated
If Ag is present on the lymphocytes, Ag-Ab complex form.
Addition of complement to the well causes cell lysis/ leaky
When dye is added, it will be taken up.
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MICRO-CYTOTOXICITY
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MIXED LYMPHOCYTE REACTION
Even when HLA compatible donor is not available, Tx may be sucessful – MLR done
To determine identity of class II HLA Ag Lymphocyte from the donor is
irradiated or treated with mitomycin C to prevent cell division – Stimulator cells
Add them to lymphocytes from the recipient – Responder cells
Radioactive nucleotide – 3H Thymidine is used
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MIXED LYMPHOCYTE REACTION
If class II Ag’s on the 2 cell population are different , the recipient cells will divide rapidly (T-cell activation) and take up large quantity of radioactive nucleotides into the newly synthesized nuclear DNA.
The amount of radioactive nucleotide uptake is roughly proportional to the MHC class II difference bw the donor & recipient .
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MIXED LYMPHOCYTE REACTION
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MLR VS MCT Advantages – Better indication of degree of TH cell
activation generated in response to class II MHC Ag of potential graft
Disadvantages - Takes several days to run the assay If potential donor is a cadaver, it is
not possible to wait for the results of MLR as organ may become non viable
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HLA I VS HLA II
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CURRENT MOLECULAR METHODS OF TISSUE TYPING
DNA analysis/ Genomic typingRestriction fragment length
polymorphism (RFLP) with southern blotting
Polymerase chain reaction amplification using sequence based primers (PCR-SSP)
Flow cytometry cross typing
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SEQ2HLA Scientists at TRON (Translational
Oncology at the University Medical Center of the Johannes Gutenberg University, Germany) have developed a new method, seq2HLA, for obtaining an individual’s HLA class I and II type and expression using standard NGS RNA-Seq data.
It comprises mapping RNA-Seq reads against a reference database of HLA alleles, determining and reporting HLA type, confidence score and locus-specific expression level
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SHOTGUN SEQUENCE Scientists at the BC Cancer Agency,
Michael Smith Genome Sciences Centre, Canada have developed a new method, – a computational method for identifying HLA alleles directly from shotgun sequence datasets.
Their approach circumvents the additional time and cost of generating HLA-specific data and capitalizes on the increasing accessibility and affordability of massively-parallel sequencing.
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IMMUNOSUPPRESSSANTS
Reduce the natural immunity of the host
Useful in – Inhibition of organ transplantation
rejection Rx of Autoimmune diseases 2 types – Generalised – Nonspecific – Increased
risk of infection & lymphoid cancers. Specific – Reduce IR to alloAg of graft –
Not yet achieved in humans.
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IMMUNOSUPRESSANTS Calcineurin inhibitors – Tacrolimus, Sirolimus,
Everolimus, Pimecrolimus.
Glucocorticoids – Prednisolone, Betamethasone,
Dexamethasone.
Nephrotoxic/ Diabetogenic
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IMMUNOSUPRESSANTS Antiproliferative/ Antimetabolite/
Cytotoxic – Cyclophosphamide,
Azathioprine, Leflunomide, Mycophenolate mofetil, Thalidomide, Methotrexate, Pentostatin, Chlorambucil, Vincristine, Cytarabine
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IMMUNOSUPRESSANTS Antibodies/ Serum –ALG – Anti lymphocyte globulinATG – Anti thymocyte globulinAnti-D immune globulin Depleting agents
Monoclonal Abx – Muronomab Depleting + Immunomodulator
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CALCINEURIN INHIBITORS - MECHANISM
Cyclosporin & Tacrolimus – Chemically different Bind to different molecular targets Do not act directly Bind to Immunophilin – C to
Cyclophilin & T to FK binding protein (FKBP-12)
After binding – Interact with calcineurin – Block its Phosphatase activity
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CALCINEURIN INHIBITORS - MECHANISM
Phosphatase activity – movement of Nuclear factor of activated T-lymphocytes (NFAT) into nucleus induces cytokines genes.
Inhibit gene transcription of IL2, IL3 and IFNgamma
C&T – Selectively inhibit CMI only and HI is maintained – Preserves general defense against infection
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CYCLOSPORINE Obtained from Beuveria nivea MC used in K, L, H Tx Given PO & IV Dose reduction in poor LFT, but not in
poor RFT Also used in GVHD after Stem cell/ BM Tx. AID – RA, Psoriasis, IBD A/E – Hyperglycemia, Hyperlipidemia,
Hirsutism, Gum hypertrophy, Tremors, Lymphoma, Kaposi’s Sa etc
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TACROLIMUS/ SIROLIMUS From Streptomyces tsukubaensis 10-100 time potent than cyclosporine Rescue therapy if cyclosporine fails No Hyperuricemia/ Hyperlipidemia
From Streptomyces hygroscopicus Binds with FKBP-12 but does not inhibit
calcineurin Blocks cell cycle G1 to S phase by inhibiting
Mammalian target of rapamycin (mTOR) No nephrotoxicity
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CYCLOPHOSPHAMIDE Cytotoxic & Most effective Destroys proliferating lymphoid
cells by alkylating property Inhibits HI>>CMI Preferred for BM Tx only A/E – Hemorrhagic cystitis dt
metabolite acrolein – Mesna Rx.
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MONOCLONAL ANTIBODIES
Low host toxicity and High specificity MAB are made using Hybridoma
technique To prevent anti-mouse Ab IR, they are
Chimerised (-ximab) or Humanised (-umab)
Use based on expression of specific Ag in certain conditions –
HER2/ NEU – Breast Ca – Tratuzumab TNF alpha – RA – Infliximab IgE – BA - Omalizumab
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MAB - CLASSIFICATION Acting on IL2 receptors –
Basiliximab*, Daclizumab*
Acting on CD cells CD3 – Muromomab* CD20 – Rituximab CD33 – Gemtuzumab CD52 – Alemtuzumab
TNF alpha – Alpha Infliximab
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MAB - CLASSIFICATION VEGF – Ranizumab EGFR – Cetuximab LFA1 – Efalizumab HER2/ NEU – Trastuzumab Platelets receptors – Abciximab IgE – Omalizumab F-glycoprotein on RSV –
Palivizumab Alpha4 integrin - natalizumab
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MAB – ADVERSE EFFECTS Rarely hypersensitivity Fever H/A Chills Arthralgia Hypotension
More during initiation/ first dose
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MAB - DISADVANTAGES
Poor tissue penetration – remain largely in vascular compartment
Short action – persist in blood 2-14d
Extremely expensive
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PROBLEMS DUE TO USE OF IS
Increased susceptibility to infection Delayed wound healing Increased risk of neoplasms
particularly lymphomas Organ toxicity such as
nephrotoxicity Others – Hypertension,
Hyperglycemia, Hypokalemia, Hyperlipidemia, Thrombocytopenia, Mouth ulcers
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INDUCTION
Agents used –CyclosporinePrednisoloneATG/ ALGAzathioprineMuromonabDaclizumab
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INDUCTION ATG is better & safer than ALG,
Muromonab Started just before Tx and continued
for 2w – 2m Regimen used depends on organ to
be Tx & toxicity of drug MC – Cyclosporine + Prednisolone +
Azathioprine In renal Tx Cyclosporine ATG If no rejection after 2w, dose reduced
and maintained If rejection – Change drugs or
Increase dose
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MAINTENANCE Drugs used –Calcineurin inhibitorsGlucocorticoidsMycophenolate mofetilChlorambucil
Multiple drugs used simultaneously
Each act at distinct site in T-cell activation
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MAINTENANCE Therapy is prolonged, very often
lifelong Continuation of induction drugs
at low doses are used If drug toxicity D/C drug
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RX OF ESTABLISHED REJECTION
Drugs used – Agents effective against activated T-lymphocytes used like
Glucocorticoids – Pulse therapy – IV Mpred 0.5-1g/d x 5d
Polyclonal ALGMuromonab
Other agents not effective against activated T-Lyphocytes
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NEWER IMMUNOSUPPRESANT
Deoxypergualin – Inhibits CTL production Mezoribine – Metabolic antagonist of
purine synthesis Biquinar sodium – Impairs pyrimidine
metabolism Leflunomide – Inhibits T cell response to
cytokines
Fusion proteins – Inhibits T cell activation Belatacept Alefacept
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PRIVILEGED SITES Allografts can be placed without
rejection reaction Anterior chamber of eye Cornea Uterus Testes Brain
These sites are characterized by an absence of lymphatic vessels and in some absence of blood vessel as well
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PRIVILEGED SITES AlloAg of graft cannot sensitize
the recipient’s lymphocytes Graft has an increased likelihood
of acceptance even when HLA Ag are not matched
Physically sequestrated graft cells from the immune system cells – by encapsulating – Current research
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FOETUS AS AN ALLOGRAFT
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PRIVILEGED SITES - FOETUS
Trophoblast in placenta do not express classical MHC Ag
Extravillous trophoblast provide adequate blood supply to the foetus
Trophoblast secrete IDO (Indo-amine dioxygenase) which destroys aa trytophan required for T cell activation
The no of alloreactive T cell is reduced in pregnancy
Trophoblast express non classical class I MHC Ag - HLA-G, which protects the foetus from NK cell-mediated lysis
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GRAFT VS HOST REACTION
Graft mounts an IR against the Ag of host
Graft contains immunocompetent T cells
Recipient possesses transplantation Ag’s that are absent in the graft
The recipient must not reject the graft
Common in BM Tx
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GRAFT VS HOST REACTION
T cells from the transplant recognize the host MHC molecules as non-self and attack the host.
This is a type IV hypersensitivity reaction
Antibody plays no role at all. Occurs in – Allograft in a recipient in whom specific
immunological tolerance has been induced
Adult lymphocytes injected into immunologically deficient recipient (Newborn)
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GRAFT VS HOST REACTION
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GRAFT VS HOST REACTION
Avoided by – PURGING Removal of all T cells from the graft
before Tx by treating with ALS/ Anti-CD3 Ab’s
Beneficial in – LEUKEMIA Moderate GvH reaction is beneficial
to destroy the residual leukemic cells which persists inspite of chemotherapy
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GRAFT VS HOST REACTION
In animal experiments – GVHD Runt’s disease Growth retardation Emaciation Diarrhea HSM Lymphoid atrophy Anemia Terminally fatal In humans – Severe inflammatory reaction, Rashes,
Diarrhea & Pneumonitis
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GRAFT VS HOST REACTION
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GRAFT VS HOST REACTION
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RECENT ADVANCES GVHD
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IMMUNOLOGICAL ENHANCEMENT
HI acts in opposition to CMI, by inhibiting graft rejection
Afferent inhibition – Ab combine with Ag released from the graft – Unable to elicit IR
Central inhibition – Ab combine with lymphoid cells – by negative feedback influence make them incapable of responding to the Ag
Efferent inhibition – Ab coat the surface of graft cells – sensitised lymphocytes cannot contact them
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An allograft will be made acceptable if recipient is made immunologically
tolerant
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IMMUNOLOGICAL TOLERANCE
Unresponsiveness to self-antigens is called immunologic tolerance
2 types – Central T/B cell & Peripheral T/B cell tolerance
Tolerance is the key factor in protecting an individual from autoimmune diseases
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TRANSPLANT TOLERANCE Unresponsiveness to donor MHC Ag by
the recipient immune system
Successful Tx is achieved only when Tx is permanently tolerated by the host
Host must retain immune competence for pathogens
Donor Ag tolerance should be stable % maintained in the recipient in the absence of immusupression
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TRANSPLANT TOLERANCE Failure to achieve permanent Tx
tolerance in spite – Understanding the process of Tx
rejection Better & safer IS drugs Improved protocol of IS
Alternative – Harness host’s own regulatory
immune mechanism & amplify them
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T REGULATORY CELLS After allogeneic Tx, along with
activation of T effector cells which causes destruction of graft, the graft protective T regulatory (Treg) cells are also generated.
The balance between the 2 subsets decides the fate of allograft
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TRANSPLANT TOLERANCE Tx tolerance should evolve strategies
for – Suppression of T effector cells Stimulation of Treg cells T effector cells are in large numbers –
controlling them is more effective Stable, perpetuating & long-lasting
Current therapeutic strategies indiscriminately inhibit alloreactive cells as well as Treg cells
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TREG CELLS Adaptive Tregs like Foxp3+, CD25+,
CD4+ are also generated in response to alloAg in Tx
Tregs prevent contact b/w T effector & Dendritic cells
Tregs are preferentially localized at sites of inflammation in the Tx where Ag is expressed
Ag specific Tregs are more effective compared to polyclonal Tregs in TX
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HURDLES IN USING TREGS Main barrier is very high frequency of
alloreactive T cells in peripheral T cell pool
Tregs like T cells are stimulated by direct & indirect pathways, the precursor frequency of these 2 cell types varies, influencing outcomes.
Surgical trauma & ischemia-reperfusion injury inflammatory signals IL-6 Inhibit conversion of CD4+ Foxp3- cells into CD4+ Foxp3+ Treg cells
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HURDLES IN USING TREGS Treg production , activation and function
has to occur in the presence of IS drugsfor allograft survival. Need to identify drugs which inhibits T effector cells while preserving and even expanding Tregs.
Drugs having such effects in-vitro – Sirolimus Mycophenolate mofetil w Vit D ATG
Tregs - Promising therapeutic modality in future
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HAEMOPOIETIC STEM CELLS
HSC – Replacement of haematopoises in many diseases like leukemia, MDS, Hemoglobinopathies
Developmental plasticity – Ability of HSC to differentiate into a variety of other tissue cell type
Transdifferentiation – Process of plasticity of adult stem cells to generate other tissue cells
Adipose derived stem cells (ASC) collected by lipoaspiration is exploited for tissue regeneration
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TRANSDIFFERENTIATION
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THANK YOUREFERENCE
Immunobiology - Janeway Immunology – Kuby Immunology – Roitt Immunology – Lippincots TB of basic & clinical Immunology –
Sontakke DNA methods for HLA typing – A
Workbook for beginners(http://www.ashihla.org/images/uploads/DNAMethodsforHLATyping%E2%80%93Workbook.pdf)