Pharm immuno14&15 cancer & transplantpor
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  • Fig. 10-1
  • CALLA: Common Acute Lymphoblastic Leukemia Antigen (CD10) sIgM – Signal IgM as sign of maturity of B cell
  • Fig 20-5
  • Fig. 20.6 Tc cells taken from a mouse immunized with a tum- variant tumor: They kill tumor cells coated with a peptide from the tum- gene sequence They do not kill tumor cells coated with the homologous peptide from the parental tumor The two peptides differ in one amino acid
  • vi. Role in immunosurveillance (T cell-deficient nude mice w/o high incidence of spontaneous tumors
  • cachectin ka-kek c tin A polypeptide cytokine, produced by endotoxin-activated macrophages , which has the ability to modulate adipocyte metabolism, lyse tumor cells in vitro, and induce hemorrhagic necrosis of certain transplantable tumors in vivo. Syn: tumor necrosis factor. Origin [G. kakos, bad, + hexis, condition of body] (SEE ABBAS, P. 367/68)
  • glycocalyx A PAS-positive filamentous coating on the apical surface of certain epithelial cells, composed of carbohydrate moieties of proteins that protrude from the free surface of the plasma membrane. Origin [glyco- + G. kalyx, husk, shell] PAS para-aminosalysylic acid.periodic acid-Schiff stain
  • Fig. 20-12 From Roitt et al
  • GM-CSF (granulocyte, macrophage-colony stimulating factor). idiotype id cT - b -t U p Collection of idiotopes within the variable region that confers on an immunoglobulin molecule an antigenic “individuality” and is frequently a unique attribute of a given antibody in a given animal. It is the product of a limited number of B lymphocyte clones ; also found on the T-cell receptor . See: idiotope [single antigenic determinant of an idiotype] . Origin [idio- + G. typos, model] idiotope id cT - b t b p Single antigenic determinant of an idiotype. See Also: idiotypic antigenic determinant. Syn: idiotypic antigenic determinant. Origin [idio- + -tope] set of idiotopes
  • Fig 10-5 Tumor-specific immune responses may be stimulated by vaccinating with host dendritic cells that have been pulsed (incubated) with tumor antigens (A) or with plasmids containing complementary DNAs encoding tumor antigens that are injected directly into patients or used to transfect dendritic cells (B) or by vaccinating with tumor cells transfected with genes encoding B7 costimulators or the T cell growth factor interleukin-2 (C)
  • FIG. 20.23, ROITT, ET AL
  • FIG 20-18
  • FIG. 20-19: ROITT ET AL -98
  • Rg. 20.20 Biological response modifiers (BRMs) are used to enhance immune responses to turnours and fall into four major groups. Broadly speaking, bacterial products have adjuvant effects on macrophages (see Chapters 17 and 19); a variety of synthetic polymers, nucleotides and polynucleotides induce IFN production and release; the cytokines administered directly act on macrophages and NK cells, and a variety of hormones including the thymic hormones can be used to enhance T-cell function. (MVE = maleic anhydride divinyl ether; TNF = tumour necrosis factor; poly 1: C = polyinosinic-polycytidylic acid.)
  • Fig 20.21 Genetically engineered chimeric Abs with human Fc portion attached to mouse Fab 2 reduce the risk of an immune response to the mAb Human Fc will also recruit human effector mechanisms Molecules that can be coupled to mAbs Toxins Cytotoxic drugs or enzymes capable of activating drugs Radioactive isotopes
  • Bone marrow containing tumor cell can be purged using mAbs and complement, Ab-toxin conjugates or Ab coupled to magnetic beads Store purged marrow Treat patient with radiation and chemotherapy Treat purged marrow with anti-tumor Ab Return bone marrow to patient Therapy results are encouraging in leukemia and lymphoma patients who where not helped by conventional therapy
  • 1- Circulating tumor markers are diagnostic: i.  -fetoprotein  hepatic carcinoma ii. Carcinoembryonic Ag (CEA)  colorectal carcinoma iii. GM1 monosialoganglioside in 96% of patients with pancreatic carcinoma 2- Monoclonal Ab to tumor surface antigens can provide a basis for imaging. Good targets include: i. F19 glycoprotein on reactive stromal fibroblasts ii. Certain tumor mucins/epithelial cancers(Thomson-Friedenreich or T antigen) iii. Cytokeratin on carcinoma cells 3- Detection of bone marrow micrometastasis using immunocytochemistry techniques provides information on: i. Prognosis ii. Efficacy of a new therapy iii. Eventual recurrence of treated cancer
  • NORMAL RANGE = 8 NG/ML
  • Parents: AA x BB Gametes: A, B F1: AB A ---to-  A & B --  B Accepted A ----  B and B ---  A Rejection 3. (Parent) A --------  F1 Hybrid: AB Result: Graft accepted because we introduce A antigen from parent to F1 recipient who has the same antigen A. No immune response needed The reverse is rejected: AB (F1) -----------  A Parent AB (F1) -----------  B Parent Result: Rejection because the recipient A does not have B antigen. Therefore, it will have immune reaction with Ab and T cells against B antigens; and Rejection because the recipient B does not have A antigen. Therefore, it will have immune reaction with Ab and T cells against A antigens. Fourth Law: Parents: AA x BB Gametes: A, B F1: AB Gametes: (A, B) x (A, B) F2: AA, 2AB, BB Transplant from any F2 individual (AA, AB, or BB) ---------  F1 Hybrid (AB) must lead to acceptance because AB has all transplanted antigens Conclusion: Genes (and antigens) of each F2 individual are represented in F1 individuals. Thus, F1 individuals have no antibodies against F2 individuals and higher generation.
  • Fig. 10-6
  • Fig 10-7
  • Fig 10-8
  • intimal Relating to the intima or inner coat of a vessel. DTH: delayed type hypersensitivity
  • III. Rejections A. Host-versus-Graft Rejection 1. First Set Rejection 2. Second Set Rejection (Acute) 3. Hyperacute Rejection 4. Chronic Graft Rejection
  • 6. Characteristics: i. Acute : epithelial cell necrosis in GI, liver and skin ii. Chronic : fibrosis and atrophy of GI, liver and skin; no epithelial necrosis

Transcript

  • 1. Pharm-Immunology-14 & 15 Immunology of Cancer & Transplants Hussein
  • 2. Introduction
    • Immunological surveillance is proposed as means of detection of transformed cells by the immune system.
    • Immune reactions could be induced at later stage and contribute to limiting of tumor development.
    • Third, therapeutic use of the immune system is more than a possibility
  • 3. Objectives
    • 1. Know the basis of immune recognition of tumors
    • 2. Know the immune responses to tumors
    • 3. Know the concept of immunosurveillance
    • 4. Know the mechanisms of immunological escape
    • 5. Understand the potential of immunological cancer therapy
    • 6. Understand the principles of immunological cancer diagnosis
  • 4. Evidence supporting the concept that the immune system reacts against tumors
    • Several lines of clinical and experimental evidence indicate that defense against tumors is mediated by reactions of the adaptive immune system
    Fig. 10-1
  • 5. Immune Recognition
    • Tumor cells undergo some changes that include some surface antigens enabling the immune system to recognize them as different from normal cells. Examples:
      • Cancers associated with viral infections might express viral encoded antigen s
      • Normally silent genes are expressed in tumor cells
        • Oncofetal antigen s :
        •  -fetoprotein ( AFP ) in hepatic cancer
        • carcinoembryonic Ag ( CEA ) in intestinal cancers
      • Ags resulting from mutations (point mutations; e.g. p5 3 )
      • Abnormal surface carbohydrates with new antigenic activity
      • Changes on the surface of cycling cells
        • Cancer cells are faster dividing than normal cells
        • Important: 95 kDa glycoprotein, F19 in sarcomas & several carcinoma
      • CALLA is an antigen associated with childhood leukemia
  • 6. CALLA (CD10)
    • C ommon A cute L ymphoblastic L eukemia A ntigen normally expressed only on B-cell progenitors (lymphoblast)
      • They make up
      • < 1% of normal bone marrow cells
    • CALLA becomes more abundant in the commonest childhood leukemia
  • 7. Immune Responses
    • T Lymphocyte s:
      • CD8 + CTLs  rejection of transplanted tumors
    • MHC I peptide presentation is necessary for recognition & killing
    • Tumor-infiltrating lymphocytes (TILs) contain CTLs capable of lysing the tumor of origin
    • CD4 + helper T cells provide:
      • cytokine s, including:
    • i) tumor necrosis factor ( TNF ),
    • ii) interferon-  ( IFN-  )
  • 8. Specificity of tumor immunity
    • Production of a highly immunogenic ( tum - ) variant tumor in DBA2 mice and Tc cells specific for it:
      • Inducing mutation by irradiating of the parent cells
      • Subclone tumor cells:
        • Some subclones ( tum - ) are no longer able to grow in DBA2 mice
        • Spleen Tc from mice injected with these tum - cells could kill tum - but not the parent tumor
    tum -
  • 9. Tc specificity
    • Tc cells taken from a mouse immunized with a tum - variant tumor: ( in vitro)
      • kill tumor cells coated with a peptide from the tum - gene sequence
      • They do not kill tumor cells coated with the homologous peptide from the parental tumor
    • The two peptides differ in one amino acid
  • 10. Immune Responses
    • Natural Killer Cells:
      • i. Kill by lysi s
        • no expression of T cell antigen receptor s
        • MHC in dependent killing
      • ii. Kill viral infected cells & hematopoietic tumors in vitro
      • iii. Express low-affinity Fc-receptors for IgG
      • iv. Cytokines (IFNs, TNF, IL-2, IL-12) increase the tumoricidal capacity of NK cells
      • v. IL-2 activated NK cells are called lymphokine-activated killer ( LAK ) cells
      • vi. Role in immunosurveillance: Nude mice w/o high incidence of spontaneous tumors
  • 11. Immune Responses
    • Macrophages mechanisms of killing :
      • release of lysosomal enzyme s
      • reactive O 2 metabolites
      • nitric oxide in mice
      • TNF secretion. By what mechanisms does TNF kill tumor cells?
        • TNF [also called cachectin] is a polypeptide cytokine, produced by endotoxin-activated macrophages , which
          • has the ability to modulate adipocyte metabolism,
          • lyse tumor cells in vitro, and
          • induce hemorrhagic necrosis of certain transplantable tumors in vivo
  • 12. Immune Responses
    • Antibodies:
    • There is some evidence that cancer patients produce antibodies against their own tumors
    • Humoral immune response is far less important than the cellular in anticancer defense
  • 13. Immunosurveillance
    • It is performed by the immune system using the same mechanisms discussed above to discover any developing cancer and destroy it
    • NK cells play an important role in surveillance
    • It does not work all the time
      • Proof: there are cancer patients
  • 14. Evasion Of The Immune System/Escape mechanisms
    • 1- Down-regulation of MHC I on tumor cells
    • 2- Lack of MHC II in human tumors  no direct activation of CD4+ helper T cells
    • 3- Lack of costimulators (B7) may impair T cell activation
    • 4- Suppression of anti-tumor immune responses by tumor products
    • 5- Host tolerance to tumor antigens due to
      • a) neonatal exposure or
      • b) presenting antigens in tolerigenic form
    • 6- Selection of mutant tumor cells lacking immunogenic peptide-MHC complexes.
    • 7- Antigenic modulation due to endocytosis or shedding of the antigen-antibody complexes
    • 8- &quot;Sneaking through&quot; phenomenon based on the kinetics of tumor growth that allow establishment of resistant tumors.
    • 9- Hiding of tumor cell surface antigens by glycocalyx molecules and others such as coagulation induction  fibrin cocoo n.
  • 15. How tumors evade immune responses?
    • Antitumor immunity develops when T cells recognize tumor antigens and are activated
    • Tumor cells may evade immune responses by:
      • losing expression of antigens
      • loosing MHC molecules
      • producing immunosuppressive cytokines
    Fig 10-4
  • 16. Tumor Ag presentation to T cells in 3 ways:
    • Directly in the absence of necessary co-stimuli , resulting in anergy .
    • Directly by a tumor which expresses co-stimulatory molecules , resulting in Tc cell activation .
    • Directly by tumor cells and indirectly via specialized APC s, resulting in activation of both Tc and T H cells
    TCR
  • 17. Cancer Immunotherapy
      • 1- Active immunization by using oncogenic viral proteins as vaccines against this class of tumors.
      • 2- Protection against some tumors can be achieved by immunization with c hronic l ymphocytic l eukemia (CLL) cells idiotype fused with GM-CSF
      • 3- Transfection of weakly immunogenic tumors with costimulatory molecules (B7) and cytokines (IFN  , IL-2, IL-4, IL-7)
      • 4- Monoclonal antibodies as magic bullets when conjugated with toxins or radionuclides to target tumor cells or antigens on malignant fibroblasts.
      • 5- Harnessing of innate immune mechanism s:
      • i. LAK against renal carcinoma;
      • ii.IFN-  and  very effective against T-cell disorders (hairy cell leukemia & mycosis fungoides);
      • less effective against Kaposi's sarcoma & various lymphomas
      • iii.Combining therapies with synergistic effects.
  • 18. Strategies for enhancing antitumor immune responses
    • Tumor-specific immune responses may be stimulated by:
    • Vaccinating with host dendritic cells that have been pulsed with tumor antigens
    • Vaccinating with plasmids containing cDNA encoding tumor Ags that are injected directly into patients or used to transfect dendritic cells
    • Vaccinating with tumor cells transfected with genes encoding B7 costimulators or the T cell growth factor IL-2
    Fig 10-5
  • 19. Pulsing of dendritic cells
  • 20.  
  • 21. Antihelminthic, immune Response enhancer
  • 22. Augmenting the host response by specific immunotherapy
  • 23.  
  • 24. Therapeutic modification of mAbs
    • Genetically engineered chimeric Abs with human Fc portion attached to mouse Fab 2
      • reduce the risk of an immune response to the mAb
      • Human Fc will also recruit human effector mechanisms
    • Molecules that can be coupled to mAbs
      • Toxins: Ricin
      • Cytotoxic drugs or enzymes capable of activating drugs
      • Radioactive isotopes
  • 25. In vitro purging of tumor-infiltrated bone marrow
    • Bone marrow containing
    • tumor cell can be purged
    • using:
    • 1. mAbs and complement ,
    • 2. Ab-toxin conjugates or
    • 3. Ab coupled to magnetic
    • beads
    • Store purged marrow
    • Treat patient with
    • radiation and chemotherapy
    • Treat purged marrow with anti-tumor Ab
    • Return bone marrow to patient
    • Therapy results are encouraging in leukemia and lymphoma patients who where not helped by conventional therapy
  • 26. Immunodiagnosis
    • 1- Circulating tumor markers are diagnostic:
    • i.  -fetoprotein ( AFP )  hepatic carcinoma
    • ii. Carcinoembryonic Ag ( CEA )  colorectal carcinoma
    • iii. GM1 monosialoganglioside in 96% of patients with pancreatic carcinoma
    • 2- Monoclonal Ab to tumor surface antigens can provide a basis for imaging . Good targets include:
    • i. F19 glycoprotein on reactive stromal fibroblasts
    • ii. Certain tumor mucins /epithelial cancers (T antigen)
    • iii. Cytokeratin on carcinoma cells
    • 3- Detection of bone marrow micrometastasis using immunocytochemistry techniques provides information on:
    • i. Prognosis
    • ii. Efficacy of a new therapy
    • iii. Eventual recurrence of treated cancer
  • 27. NORMAL RANGE 
  • 28. Immune Response Against Transplant
    • Know the evidence for the immune nature of transplant rejections
    • Describe MHC Ags as the principal targets of rejection
    • Know the the types of graft rejection:
      • Acute
      • Hyperacute
      • Chronic
    • Understand the role of immunosuppressive drugs such as cyclosporine in organ transplantation
    • Describe the principle of mixed lymphocyte reaction (MLR)
    • Know blood transfusion
    • Know the bone marrow transplantation and the associated graft-versus-host (GvH) disease
  • 29. Types of grafts
    • Syngeneic grafts ( syngraft )
      • Donor and recipient are genetically identical  No rejection
        • Identical twins
        • Inbred mice
        • Their Ags are called isoantigens
        • Isoantibodies
    • Allogeneic grafts ( allograft )
      • Donor and recipient are genetically different members of the same species  Rejection
        • Their Ags are called alloantigens
        • Their Abs & T cells are alloreactive (alloantibodies)
    • Xenogeneic ( xenograft )
      • Donor and recipient are from different species  Rejection
        • Their Ags are called xenoantigens
        • Their Abs & T cells are xenoreactive
  • 30. Types of Grafts
    • Autograft: Autogenic, autologous tissue
    • A. Syngraft: Syngeneic tissue
    • B. Isograft: Isologous tissue
    • Allograft (Homograft): Allogeneic tissue
    • Xenograft (Heterograft): Xenogeneic (Heterologous) tissue
  • 31. Transplantation Laws
    • Syngrafts are accepted
    • Allografts are rejected
    • Transplants from parent to F1 hybrid are accepted; reverse rejected
    • Transplants from F2 individuals to F1 are accepted*
    • Transplants from either parent are mostly rejected, but accepted in some
  • 32. Evidence indicating that the rejection of tissue transplants is an immune reaction
    • Clinical and experimental evidence indicates that rejection of grafts is a reaction of the adaptive immune system
  • 33. Recognition of allogeneic MHC molecules by T lymphocytes.
    • Recognition of allogeneic MHC molecules may be thought of as a cross reaction in which a T cell specific for a self MHC molecule-foreign peptide complex (A) also recognizes an allogeneic MHC molecule whose structure resembles that of a self MHC molecule-foreign peptide complex (B, C)
    • Donor peptides derived from the graft may not contribute to allorecognition (B), or
    • They may form part of the complex that the T cell sees (C)
    • The type of T cell recognition depicted in B and C is called direct allorecognition
  • 34. Direct and indirect recognition of alloantigens
    • A. Direct alloantigen recognition occurs when T cells bind directly to intact allogeneic MHC molecules on professional APCs in a graft
    • B. Indirect alloantigen recognition occurs when allogeneic MHC molecules from graft cells are taken up & processed by recipient APC
    • and peptide fragments of the allogeneic MHC molecules are presented by recipient (self)
    • MHC molecules
    • Recipient APCs may
    • also process &
    • present graft proteins
    • other than allogeneic
    • MHC molecule
    Graft APC
  • 35. Mechanisms of graft rejection: Hyperacute rejections
    • In hyperacute rejection, preformed antibodies react with
      • alloantigens on the vascular endothelium of the graft,
      • activate complement , and
      • trigger rapid intravascular thrombosis and necrosis of the vessel wall
  • 36. Mechanisms of graft rejection: Acute rejection
    • In acute cellular rejection , CD8 + T lymphocytes reactive with alloantigens on graft endothelial cells and parenchymal cells cause damage to these cell types
    • Endothelium inflammation is sometimes called &quot; endothelialitis &quot;
    • Alloreactive antibodies may also contribute to vascular injury
  • 37. Chronic Graft Rejection
    • Months or years after Transplant
    • Example:
      • Kidneys gradual loss of function
    • Biopsy reveals rejection process while progressing slowly
  • 38. Mechanisms of graft rejection: Chronic rejection
    • In chronic rejection with graft arteriosclerosis , T cells reactive with graft alloAgs produce cytokines that induce endothelial & intimal smooth muscle cells proliferation, leading to luminal occlusion
    • This is probably a chronic DTH reaction to alloantigens in the vessel wall
  • 39.  
  • 40. Graft Rejection Displays Immunological Memory
    • Left:
      • A human skin allograft @ day 5 is fully vascularized & cells are dividing
    • Middle:
      • Graft is totally destroyed by day 12
    • Right:
      • Second-set graft from the same donor fails to vascularize and is destroyed rapidly by day 7 because the first graft sensitized the recipient  Immunological memory
  • 41. Graft-versus-Host Reaction (GvHR)
    • The graft rejects the host
    • Graft cells are immunocompetent
    • Recipient is immuno in competent
    • Conditions for GvHR:
    • i. Histo in compatibility
    • ii. Transfer of immunocompetent (T) cells
    • iii. Immunodeficient recipient
    • 5. GvHR occurs after bone marrow transplantation for stem cell replacement in:
    • i. Aplastic anemia
    • ii. Acute leukemia
    • iii. Combined immunodeficiencies
  • 42. Mixed lymphocyte reaction
    • MLR is an in vitro test for T cell recognition of alloantigens
    • T cells from the potential recipient of a transplant are cultured with WBCs from the potential donor
    • The response of the T cells is assayed
      • If the response with lysis and cell damage is strong the matching between the two individuals is weak
      • The weaker the response, the greater the match
    • This is a rough predictor of the transplant’s outcome: rejection or acceptance
  • 43. ABO blood groups & blood transfusion
    • Blood group Ags are a major barrier for blood transfusion
    • ABO Ags are glycosphingolipids mainly on surface of RBC
      • Group A has N-acetylgalactoseamine Ag & anti-B Ab
      • Group B has galactose Ag & anti-A Ab
      • Group AB has both Ags & no Abs
      • Group O has neither Ag & both Abs (anti-A & anti-B)
      • Transfusion reaction occurs when donor has Ags that are not present in the recipient
    • The Abs are sometimes called natural Abs and thought to be made against intestinal bacteria and capable of cross-reaction with the blood group Ags
    • Rh groups are important especially in cases of pregnancy where the mother is Rh - and the baby is Rh +
      • In the second pregnancy the baby will have problems of blood lysis
  • 44. Treatments for graft rejection
    • Agents that are commonly used to treat the rejection of organ grafts, and the mechanisms of action of these agents, are listed
    • FK506 is a drug that works like cyclosporine , but FK506 is not used as widely
    Brendan Doran ( Tacrolimus )
  • 45.