Immune Response
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Immune Response



Immune Response

Immune Response



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Immune Response Immune Response Presentation Transcript

  • Human Body is a Complex Structure Dr.T.V.Rao MD 2
  • Immune System Controls the Immune Responses Dr.T.V.Rao MD 3 View slide
  • Dr.T.V.Rao MD 4 View slide
  • Organs of Immunity Coordinate different functions Dr.T.V.Rao MD 5
  • Immunity is a less Understood Puzzle Dr.T.V.Rao MD 6
  • Dr.T.V.Rao MD 7
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  • Path of Immune Response Dr.T.V.Rao MD 9
  • Immune Response Protects Dr.T.V.Rao MD 10
  • 11Dr.T.V.Rao MD 11
  • Immune Response –A complex Mechanisms Dr.T.V.Rao MD 12
  • Several Cell Interactioncompromises the Immune Response Dr.T.V.Rao MD 13
  • B Cells and T Cells work in Coordination Dr.T.V.Rao MD 14
  • Immune response works at Cellular level Dr.T.V.Rao MD 15
  • 16 The Immune response• An immune response is what the immune system does when confronted by an antigen.• An immune response is an elaborate interplay between antigen, non-specific defenses, and B and T lymphocytes.• The process involves direct contact (cells, molecules bind to receptors on cell surfaces) and cytokines (messenger molecules) that also bind to receptors on cell surfaces. Dr.T.V.Rao MD 16
  • Results of Immune Response• Beneficial,• Indifferent,• Injurious, Reactions follow against any antigen either living or dead.May respond in Specific or No reactivity or Tolerance. Dr.T.V.Rao MD 17
  • Classification of Immune Response 1 Humoral 2 Cell Mediated type• May work together.• May work in opposite way,• One may be more active than other. Dr.T.V.Rao MD 18
  • Immune Response Humoral / Cell Mediated Active against Most Protects against,Extra cellular Bacterial Fungus, Viruses IC pathogens bacterial infectionsViruses, Rejection of HomograftParticipates in Type ,GVH,1 , 2, 3, Hypersensitivity Immunological reactions survelliance,cancerAuto Immune Disorders. T cell mediated Hypersensitivity Auto Immune Disorders Dr.T.V.Rao MD 19
  • Structure of Immunoglobulin Dr.T.V.Rao MD 20
  • Humoral Immune Response• Produces Antibodies B Cell – Plasma cell• Antigen Presented to Immunocompetent cells Processed –• Secretion of Antibodies, Dr.T.V.Rao MD 21
  • Production of Antibodies• Immune response is brought about by three types of cells• 1 APC macrophages, and dendritic cells,• 2 T Cell and 3 B cells• The first step is capture and processing of antigens by APC and their presentation with the association of appropriate MHC molecule to T cells• However some polysaccharides and simple molecules with repeating epitopes do not require T Cell participation Dr.T.V.Rao MD 22
  • Stages of Antibody mediated immune response• Contain three stages 1 The entry of antigen, its distribution and fate in the tissues and its contact with appropriate immunocompetent cells 2 The secretion of antigen by cells and the control of the antibody forming process 3 The secretion of antibody its distribution in tissues and body fluids and manifestations of its effects. Dr.T.V.Rao MD 23
  • Pathogens damage tissue in a variety of ways * *e.g., LPS; a polyclonal B cell Dr.T.V.Rao MD 24 activator, also see next slide
  • Pattern of Antibody production.• A Lag Phase• A Log Phase raise of antibody levels,• Plateau• A phase of Dr.T.V.Rao MD 25 Decline.
  • Primary and Secondary Immune Responses • A single injection of antigen helps in sensitizing or priming of immunocpompent cell producing particular antibody than in the actual elaboration of high levels of antibody. • Effective levels of antibody are usually induced by only subsequent injection of antigens. Dr.T.V.Rao MD 26
  • Booster Dose• The antibody response to an initial antigenic stimuli differs qualitatively and quantitatively from response to subsequent stimuli with the same antigen• The former primary response and later secondary response Dr.T.V.Rao MD 27
  • Primary and Secondary Response • The primary response is slow, sluggish and short lived with long lag phase and does not persist for long time • The secondary response is prompt powerful and prolonged with short or negligible lag phase and with higher level of antibodies Dr.T.V.Rao MD 28
  • Types of Antibody Response,• Initial Antigenic Stimulus (Primary Response Ig M• Response is slow and short lived,• Secondary Response Ig G• Response is Prompt ,Powerful and Prolonged Higher level of Antibodies and Lasts longer, Dr.T.V.Rao MD 29
  • How long a Antibody be active• The duration of the lag phase and persistence of the antibody dependent on the nature of the antigen• In diphtheria toxoid the lag phase in the primary response may be long as 2 -3 weeks• In pneumococcal polysaccharides antigens the antibodies are detected Dr.T.V.Rao MD 30 in few hours
  • Priming and Booster doses• The first injection is known as priming dose and subsequent injection as booster dose.• With live vaccines a single dose is sufficient a single dose is sufficient as multiplication of the organisms in the body provides a continuous antigenic stimulus that acts as both the priming and booster dose Dr.T.V.Rao MD 31
  • Fate of Antigens• Depends on the physical and chemical nature of antigens, dose and route of entry• Whether induced primarily or secondarily• The antigens introduced by IV are rapidly localized in the spleen, liver, bone marrow kidney and lungs• Broken down by RES cells excreted in urine• About 70 – 80 % Dr.T.V.Rao MD eliminated in one or two 32 days
  • Fate of Antigens• When antigens are introduced by subcutaneously are mainly localized in the draining lymph nodes only small amounts being found in the spleen• The pariculate antigens are removed from circulation in two phase – the first is antigens are engulfed by phagocytic cells broken down and Dr.T.V.Rao MD 33
  • Fate of Antigen• With the appearance of specific antibody the phase of immune elimination begins• The antigen and antibody complexes are rapidly phagocytized results in disappearance of antigen from circulation Dr.T.V.Rao MD 34
  • Immunoglobulin controlling genes and Generation of Diversity.• Genes control Antibody production and Diversity,• V and C regions• Kappa light chain / Lambda light chain• Rearrangements produce enormous diversity variety of Immunoglobulin• Combinations produce random selections. Dr.T.V.Rao MD 35
  • Immunoglobulin Switching.• Ig M specific for Antigen is produced.• Switch to others Ig G - Ig A -Ig EBut retain the same specificity,But carry different Biological activities Dr.T.V.Rao MD 36
  • Relation of Dose and Nature of Antigen to Antibody production.• Single Dose Sensitizing.• Subsequent Dose More effective.• Non Living Vaccines multiple doses.• Living Vaccines one Dose is productive.• Fate of Antigen I V eliminate faster, in 2-3 days, in spleen. SC Lymph nodes Little in spleenEngulfed by Phagocytes Broken Down and eliminated. Dr.T.V.Rao MD 37
  • Fate of Antigen in the Host• Ag+Ab from complexes and Phagocytes will engulf and Disappear -- Immune Elimination. Immune Complexes can cause damage.Proteins eliminated in 1-2 weeks,Polysaccharides months to years.Pneumococcal polysaccharides up to 20 years. Dr.T.V.Rao MD 38
  • Production of Antibodies.• Immune Responses to Antigen,• Antigen Presenting Cells APC Macrophages Dendritic Cells T and B Lymphocytes, Capture by APC ( Proteins RBC ) T Cell take active part. T Cell Independent - Polysaccharides. Dr.T.V.Rao MD 39
  • Production of Antibodies needs help and coordination with other structures• CD4 Helper cells MHC II• CD8 Cytotoxic cells MHC• TH cells require two signals IL1• Next produce IL2 Produce cytokines IL4 IL5 IL6 B cells stimulatedProduce antibody producing plasma cells produced Dr.T.V.Rao MD 40
  • Factors InfluencingAntibody production Dr.T.V.Rao MD 41
  • Factors Influencing Antibody Production• Under genetic control,• May be responder or Non responder.- defines the capacity of the individual to respond or not respond• Ir (Immune response genes) control this property.• Age The embryos is immunologic ally immature During the embryonic life the developing lymphoid cells come into contact with all the tissue antigens of the body released by cellular breakdown – lead to elimination of self antigens Dr.T.V.Rao MD 42
  • Immunity in NeonatesEarly mechanisms of self tolerance. -> 3-6 months Maternal antibodies, Ig G 5-7 years Ig A 10-15 yearsB cell responses to most proteins and other T cells dependent develop early.The responses to Polysaccharide and other T cell independent antigens develop later. Dr.T.V.Rao MD 43
  • Humoral Immunity in vivo uses• Immunoglobulin IgA can stop colonization of mucosal surface.• It interferes with the attachment molecular adhesions present on the bacterial surface.• Bacterial exotoxins are inhibited – as the antibodies can prevent interaction of enzymes with substrate. Dr.T.V.Rao MD 44
  • Humoral immunity in vivo uses• Antibodies can kill bacteria.• Antibodies can affect the specific transport systems and deprive the energy needs of the bacteria.• Affect the motility• Reduces the invasion• Antibodies can cause agglutination• Stimulate the phagocytosis, and complement activity. Dr.T.V.Rao MD 45
  • Other Factors influencing the Antibody production• Nutrition Malnutrition Humoral reduced, CMI reducedRoute of administrationLarge particles – increased.Application to skin CMIDeltoid more effective Dr.T.V.Rao MD 46
  • Other factors,• Size and Dose has relation• Massive Dose paralysis.• Anamnestic reaction• Administration of Multiple antigens Triple antigen,Freund’s Adjuvant. Increases with Tubercle Bacilli Dr.T.V.Rao MD 47
  • Uses of Administration of Antibodies• Passive administration of Antibodies eg Hyper immune globulins, Sensitization issues in Rh negative mothers.The effect occurs due to feedback mechanismThe antibody may also combine with antigen and prevent its availability for the immunocompetent cells.Rh –ve mother + Rh+ ve fetus Administration of Anti-Rh globulin immediately following delivery Dr.T.V.Rao MD 48
  • Administration of Immunoglobulins• IV administration has immunomodulation effect• Administered in Thrombocytopenias, and autoimmune hemolytic anemia. Dr.T.V.Rao MD 49
  • Adjuvants• Defined as substance that enhances the immunogenicity of an antigen.• Eg Aluminum hydroxide or phosphate• Freund’s incomplete adjuvant – Incorporation of protein antigen in water phase of water in oil emulsion, it causes delay of release of antigen from the site of injection and prolong the antigenic stimulus.• Freund’s complete adjuvant – contains also the suspension of killed tubercle bacilli.• The effect is due to MDP ( muramyl dipeptide ) Dr.T.V.Rao MD 50
  • Super antigens,• Protein Molecules, eg Staphylococcal Enterotoxin, Activate large number of T cells, Irrespective of Antigenic specificity, Usually few cells are stimulated ( 0.001%)Massive stimulation leads to Massive out porins of T cell cytokines,Multi organ DysfunctionStaphylococcal Shock syndrome Dr.T.V.Rao MD 51
  • Super antigens,• Protein Molecules, Eg Staphylococcal Enterotoxin, Activate large number of T cells, Irrespective of Antigenic specificity, Usually few cells are stimulated ( 0.001%)Massive stimulation leads to Massive out pouring of T cell cytokines,Multi organ DysfunctionStaphylococcal Shock syndrome Dr.T.V.Rao MD 52
  • Immunosuppressive Agents• X rays,• Corticosteroids• Anti metabolites.• Cytotoxic Chemicals Dr.T.V.Rao MD 53
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  • Superatigens stimulates several lymphocytes Dr.T.V.Rao MD 55
  • Monoclonal Antibodies• Kohler and Milstein ( Nobel Prize 1984 )• A single antibody forming cell or clone produces Antibodies against single antigen,• Antibodies are usually polyclonal,• Clone of Lymphocytes – Monoclonal antibodies. Useful in Diagnostic / Research work. Dr.T.V.Rao MD 56
  • How Hybridoma Created.• Immunize Mice with Antigen,• Obtain spleen cells Fuse with Mouse Myeloma cellsGrow then in HPRT medium Hypoxanthine,Phosphorib osyl transfeeraseTransfer to HAT Medium ) Hypoxanthine, Aminoptre n and Thymidine Medium }Lead to formation of Hybridoma. Dr.T.V.Rao MD 57
  • Hybridoma TechnologyProduce Monoclonal Antibodies What is Hybridoma Fusion of Spleen cells + Myeloma Cells,Attains the capacity to produce 1. Antibody producing capacity. 2. Multiply indefinitely, Dr.T.V.Rao MD 58
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  • Contents of Hybridoma• Splenic cells + Myeloma cells Produce Monoclonal Antibodies,Propagated by injecting intraperitoneallyIn Mice -FrozenMonoclonal are similar in Ig class and other characters. Dr.T.V.Rao MD 61
  • Uses of Monoclonal Antibodies1 Research applications,2. Diagnostic.3.Theraputic,Mice Monoclonal are suitable for Humans,Chimeras antibodies are created.Grafting of Murine Monoclonal on CDR loops.Antibodies can be used with BacteriophagesAdvances in Immunotherapy. Dr.T.V.Rao MD 62
  • Immune Response in Cell mediated Immunity CMIT Lymphocytes play the major role Dr.T.V.Rao MD 63
  • CMI helps in• Delayed hypersensitivity• Immunity in infections caused by Obligate and facultative intracellular parasites• Eg – Tuberculosis, Leprosy Listeriosis, Brucellosis, Fungi – Histoplasmosis, Cocccidiomysosis,Blastomycosis, Parasites – TrypanosomiasisIn transplantation immunity, Immunologioly in Transplantation, malignancy,Pathogenesis of Autoimmune diseases Dr.T.V.Rao MD 64
  • Induction of Cell Mediated Immunity• Depends on Nature of Antigenic stimulus• Best developed after following infection with intracellular parasites• Live vaccines highly stimulating• Killed vaccine not very effective• But effective if contains Freund type adjuvant. Dr.T.V.Rao MD 65
  • 66Dr.T.V.Rao MD 66
  • Functions of T cells• Only T cell dependent antigens lead to development of CMI• Certain chemicals which come in contact with skin induces Delayed hypersensitivity• T Cell contain the specific receptor ( TCR )• One epitope ( Antigen ) on contact with receptor undergoes blast transformation• Leads to Clonal proliferation Dr.T.V.Rao MD 67
  • Functions of T cells• Cytotoxic T cells recognize antigen on surface of virus infected cells, tumor cells, allograft cells with MHC I and sectored Lymhokines and destroy target cells MD Dr.T.V.Rao 68
  • Functions of T cells• The stimulated cells undergoes blast transformation, Clonal proliferation• Leads to Effectors cells and Memory cells• T cell react on presentation with MHC• Helper T cells when presented on surface of macrophages or other cells complexes with MHC II molecule – leads to release of Biological Mediators Lymhokines – activate Macrophages and kills intracellular parasites Dr.T.V.Rao MD 69
  • Broad view on Cytokines• Cytokines are a category of signalling proteins and glycoproteins that, like hormones and neurotransmitters, are used extensively in cellular communication Dr.T.V.Rao MD 70
  • Cytokines• Cytokines have been classed as Lymhokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for Dr.T.V.Rao MD 71
  • Definitions• Lymhokines Biologically active substance released by activated T Lymphocytes• Monokines – Substances secreted by Monocytes and Macrophages• Interleukins – Produces by lymphocytes which exert a regulatory effect on other cells• All above grouped under cytokines Dr.T.V.Rao MD 72
  • Definitions• Autocrine, if the cytokine acts on the cell that secretes it.• Paracrine, if the target is restricted to the immediate vicinity of a cytokines secretion.• Endocrine, if the cytokine diffuses to distant regions of the body (carried by blood or plasma).• It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses. Dr.T.V.Rao MD 73
  • What are Cytokines• They are peptide mediators, intracellular messengers, which regulate immunological, inflammatory and reparative host cell responses• They are potent hormones Active even at Fetomolar concentrations produced by widely distributed cells ( Lymphocytes, Macrophages, Platelets, an d Fibroblasts. Dr.T.V.Rao MD 74
  • Cytokines• Cytokines may act on the cells that secrete them (Autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action) Dr.T.V.Rao MD 75
  • Cytokines have• Paracrine effect – acts locally – near the producing cells• Having pleotrophic effects – Multiple effects on growth and differentiation of various cell types. Dr.T.V.Rao MD 76
  • Important Cytokines• Interleukin I 1979• Interleukin I divided into Alpha and Beta• IL1 is secreted by Macrophages, Monocytes other nucleated cells.• Stimulated by Antigens, Toxins, Injury, Inflammation,• Inhibited by• Cyclosporins,Corticosteiods,Prostaglandins Dr.T.V.Rao MD 77
  • Functions of Interleukin 1• IL1 stimulates T cells and Produces IL2 and other Lymhokines• Helps B cell proliferation• Synthesizes Antibodies• Helps Neutrophils in Chemo taxis• Promotes Phagocytosis• Promotes Metabolic Physiological and inflammatory responses by action on Bone marrow Dr.T.V.Rao MD 78
  • IL1 initiates Fever• IL1 is crucial in promoting fever and called as Pyrogens.• With the help of Tumor Necrosis factor causes hematological changes in Septicemias, Shock and bacterial meningitis Dr.T.V.Rao MD 79
  • Other Interleukins• Interleukins 2 Modulates the immune response• Major activator of T and B Lymphocytes• Stimulates cytotoxic T cells and Natural Killer cells.• Interleukin 3 Stimulates multilineage cells of the Hematopoietic system. Dr.T.V.Rao MD 80
  • Other Interleukins• Interleukin 4 Acts as a Growth factor for T Lymphocytes• Interleukin 5 Causes the proliferation of activated B Lymphocytes• Interleukin 6 Produced by Stimulated B and T Lymphocytes Induces the production of Immunoglobulin synthesis Stimulates the Hepatocytes, nerve cells,Hematopoetic cells Dr.T.V.Rao MD 81
  • Theraputic Uses of Cytokines• IL1,2,3 and colony stimulating factors are used in Inflammatory diseases, Infections, Autoimmune diseases. Neoplastic diseases and cancers Dr.T.V.Rao MD 82
  • Mechanisms in Inflammatory Response Dr.T.V.Rao MD 83
  • Mechanisms in Inflammatory Response Dr.T.V.Rao MD 84
  • Functions of Cytokines• Autocrine, if the cytokine acts on the cell that secretes it.• Paracrine, if the target is restricted to the immediate vicinity of a cytokines secretion.• Endocrine, if the cytokine diffuses to distant regions of the body (carried by blood or plasma).• It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses. Dr.T.V.Rao MD 85
  • Properties of Cytokines• Cytokines are small secreted proteins which mediate and regulate immunity, inflammation, and hematopoiesis. They must be produced de novo in response to an immune stimulus. They generally (although not always) act over short distances and short time spans and at very low concentration. Dr.T.V.Rao MD 86
  • Properties of Cytokines• They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behaviour (gene expression). Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation, and secretion of effector molecules. Dr.T.V.Rao MD 87
  • Properties of Cytokines• Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Dr.T.V.Rao MD 88
  • Properties of Cytokines Dr.T.V.Rao MD 89
  • Other Cytokines• Other groups of cytokines include interferons and chemokines. Interferons IFNa and IFNb inhibit virus replication in infected cells, while IFNg also stimulates antigen-presenting cell MHC expression. Chemokines attract leukocytes to infection sites. Chemokines have conserved cysteine residues that allow them to be assigned to four groups. Dr.T.V.Rao MD 90
  • Inhibitory Cytokines• Some cytokines are predominantly inhibitory. For example, IL-10 and IL-13 inhibit inflammatory cytokine production by macrophages. Dr.T.V.Rao MD 91
  • Interferons• Primarily identified as Antiviral agents• Now classified as Cytokines• Interferons play an important role in the first line of defence against viral infections. They are part of the non-specific immune system and are induced at an early stage in viral infection – before the specific immune system has had time to respond.. Dr.T.V.Rao MD 93
  • Dynamics of Interferons• Interferons are made by cells in response to an appropriate stimulus, and are released into the surrounding medium; they then bind to receptors on target cells and induce transcription of approximately 20-30 genes in the target cells, and this results in an anti-viral state in the target cells. Dr.T.V.Rao MD 94
  • Classification of Interferons• There are three classes of Interferons: Alpha, Beta and Gamma. Interferon Alpha and Beta are produced by many cell types Dr.T.V.Rao MD 95
  • Types of Interferons• Interferon-alpha (leukocyte interferon) is produced by virus-infected leukocytes, etc• Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or virus-infected epithelial cells, etc• Interferon-gamma (immune interferon) is produced by certain activated T-cells and NK cells.• Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes. Dr.T.V.Rao MD 96
  • Functions of Interferons• Interferons are within the cytokine family of proteins. Interferons are especially important because they enhance the immune system’s ability to recognize foreign invaders, enabling the system as a whole to function more effectively Dr.T.V.Rao MD 97
  • Interferons Gama• Interferon-Gamma is involved in the regulation of immune response throughout the body. Interferon-Gamma is the signalling protein that gets the immune system as a whole ready for attack and fine tunes it to quickly and effectively get rid of foreign and unwanted intruders Dr.T.V.Rao MD 98
  • Uses of Interferons• Interferons-alpha and -beta have been used to treat various viral infections. One currently approved use for various types of interferon-a is in the treatment of certain cases of acute and chronic hepatitis C and chronic hepatitis B. Dr.T.V.Rao MD 99
  • Uses of Interferons• Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis. Since interferons have anti-proliferative effects, they have also been used to treat certain tumours such as melanoma and Kaposi’s sarcoma. Dr.T.V.Rao MD 100
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  • Detection of CMI• The basic and earlier test was skin test for delayed hypersensitivity• Now other tests are available Lymphocyte transformation test Migration inhibiting factor test. Dr.T.V.Rao MD 103
  • Theories of Immune Response• Several theories are considered1 Direct template theory2 Indirect template theory3 Natural selection theory4 Clonal selection theory Dr.T.V.Rao MD 104
  • What is Clonal Selection Theory• Burnet proposed the theory 1957• The theory emphasizes the immunological specificity to cellular level In this theory the cell are formed by somatic mutation, the cells that react with self antigens are eliminated and called as Forbidden clones. Their persistence in later life leads to Autoimmune process Dr.T.V.Rao MD 105
  • Jerne’s network hypothesis• It explains the mechanism of antibody response• The variable region of an immunoglobulin molecule carrying the antigen combining site is different in different antibodies• The distinct Aminoacid sequence at antigen combing site and the adjacent parts of the variable regions are termed as idiotype• Produce antiidotypic antibodies• Which in turn produce antibodies to them Dr.T.V.Rao MD 106
  • Nobel Prize winning theory• Which in turn produce antibodies to them• Forms a idiotype network• The above process controls the amount of antibodies• The above theory by Niels K.Jerne was awarded Nobel Prize for Medicine in 1984 Dr.T.V.Rao MD 107
  • Recent Theories• Now genetic basis of antibody diversity is identified.• The recent theory of Split genes explains many unknown mechanisms• The theory says the information occurs in discontinuous stretches of DNA, each coding for separate regions of the antibody molecule Dr.T.V.Rao MD 108
  • • Programme created byDr.T.V.Rao MD for Medicalstudents in the Developing World • Email • Dr.T.V.Rao MD 109