Immunology of transplantation with MHC

IMMUNOLOGY OF TRANSPLANT

DR R SATHYAJITH

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.

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.

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.

TYPES

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.

TYPES Stored or Fresh.

Living or Cadaveric donor.

Live grafts/Vital grafts - Kidney, Heart.

Non living - Bone, Artery.

Static or Structural grafts.

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.

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

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

MAJOR HISTOCOMPATIBILITY COMPLEX

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

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

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

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

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

CLASS I MHC

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

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)

INHERITANCE OF MHC LOCUS

M/N Q/R

M/Q M/R N/Q N/R 2% Genetic Recombination

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

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

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

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.

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

GRAFT REJECTION

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.

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

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.

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

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

MECHANISM OF GRAFT REJECTION

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

HYPERACUTE REJECTION

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

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

ACUTE GRAFT REJECTION

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

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

CHRONIC REJECTION

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

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.

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

PEARLS - SUCCESSFUL TRANSPLANTATION

Tx dysfunction monitoring & Rx of established rejection

Withdrawal or reduction of dose of a drug whenever toxicity outweighs the benefits

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)

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.

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

HLA TYPING

Classically done using –

Micro-cytotoxicity (MCT)Mixed lymphocyte reaction (MLR)

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.

MICRO-CYTOTOXICITY

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

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 .

MIXED LYMPHOCYTE REACTION

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

HLA I VS HLA II

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

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

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.

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.

IMMUNOSUPRESSANTS Calcineurin inhibitors – Tacrolimus, Sirolimus,

Everolimus, Pimecrolimus.

Glucocorticoids – Prednisolone, Betamethasone,

Dexamethasone.

Nephrotoxic/ Diabetogenic

IMMUNOSUPRESSANTS Antiproliferative/ Antimetabolite/

Cytotoxic – Cyclophosphamide,

Azathioprine, Leflunomide, Mycophenolate mofetil, Thalidomide, Methotrexate, Pentostatin, Chlorambucil, Vincristine, Cytarabine

IMMUNOSUPRESSANTS Antibodies/ Serum –ALG – Anti lymphocyte globulinATG – Anti thymocyte globulinAnti-D immune globulin Depleting agents

Monoclonal Abx – Muronomab Depleting + Immunomodulator

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

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

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

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

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.

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

MAB - CLASSIFICATION Acting on IL2 receptors –

Basiliximab*, Daclizumab*

Acting on CD cells CD3 – Muromomab* CD20 – Rituximab CD33 – Gemtuzumab CD52 – Alemtuzumab

TNF alpha – Alpha Infliximab

MAB - CLASSIFICATION VEGF – Ranizumab EGFR – Cetuximab LFA1 – Efalizumab HER2/ NEU – Trastuzumab Platelets receptors – Abciximab IgE – Omalizumab F-glycoprotein on RSV –

Palivizumab Alpha4 integrin - natalizumab

MAB – ADVERSE EFFECTS Rarely hypersensitivity Fever H/A Chills Arthralgia Hypotension

More during initiation/ first dose

MAB - DISADVANTAGES

Poor tissue penetration – remain largely in vascular compartment

Short action – persist in blood 2-14d

Extremely expensive

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

INDUCTION

Agents used –CyclosporinePrednisoloneATG/ ALGAzathioprineMuromonabDaclizumab

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

MAINTENANCE Drugs used –Calcineurin inhibitorsGlucocorticoidsMycophenolate mofetilChlorambucil

Multiple drugs used simultaneously

Each act at distinct site in T-cell activation

MAINTENANCE Therapy is prolonged, very often

lifelong Continuation of induction drugs

at low doses are used If drug toxicity D/C drug

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

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

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

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

FOETUS AS AN ALLOGRAFT

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

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

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)

GRAFT VS HOST REACTION

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

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

GRAFT VS HOST REACTION

GRAFT VS HOST REACTION

RECENT ADVANCES GVHD

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

An allograft will be made acceptable if recipient is made immunologically

tolerant

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

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

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

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

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

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

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

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

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

TRANSDIFFERENTIATION

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)