Immune Response Against Tumors and Transplant

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Chapter 10

• Immune Response Against Tumors and Transplant
• Immunity to Non-Infectious Transformed and
  Foreign Cells

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New Areas for Immunity

• Cancer
• immune response against tumor
• Tissue transplant
• need to suppress immune response
• Both share several characteristics
• not against microbes but non-infectious cells
  that are perceived as foreign
• Ag to mark tumor and transplant as foreign are
  expressed in any cell type that is target of
  malignant transformation or from one individual
  to another
• important mechanism to damage cell is CTLs

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Immune Response Against Tumors

• Adaptive immune response to prevent outgrowth of
  transformed cells before become tumors immune
  surveillance
• important against tumor growth
• not strong enough against rapid growing tumors

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Tumor Antigens

• Malignant tumors express various molecules that
  may be recognized as foreign may lead to immune
  response
• Ag expressed on tumors as non-self by immune
  system
• may be mutants of cellular proteins, in
  experimental tumors
• not part of tumorgenesis
• not seen as commonly in spontaneous human tumors
• may be proteins responsible for tumorgenesis
• may be normal protein that is over-expressed, or
  limited to a specific tissue or stage of
  development
• embryonic tissues may not have tolerance in adult
  tissue

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Tumor Ag
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Tumor Rejection

• Immune mechanisms to cause tumor eradication is
  by killing with CTLs specific for tumor Ag
• tumor Ag are endogenously cytoplasmic synthesis
  displayed in MHC I associated peptides CD8
  T-cell
• seen in animal models tumor transplants
  destroyed by transferring tumor reactive CTLs to
  animal
• CTL response induced by recognition of tumor Ag
  on host APC by ingesting tumor cells or Ag and
  presented to T-cells
• any nucleated cell can become a tumor cell and
  can express MHC I, usually no costimulators or
  MHC II which are needed for naïve T-cell to mount
  response

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Cross-Priming

• Likely mechanism is tumor cell is phagocytosed by
  professional APC
• Ag on MHC I or MHC II regular activation of
  CD4 or CD8 cells (professional APC make
  costimulatory molecules)
• called cross-presentation or cross-priming
• professional APC take Ag from other cells and
  primes T-cells specific for 2nd cell
• used for vaccination against tumor active CD8
  to CTL to kill tumor cells

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Cross-Priming T-Cells
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Evasion of Immune Response

• Immune response often fail because they are
  ineffective or tumors can evade immune attack
• Not able to kill all tumor cells because of such
  rapid growth of tumor, tumor Ag may only weakly
  immunogenic
• Develop mechanisms to evade immune system
• stop making tumor Ag
• Ag loss variant
• if not part of tumor tumor continues to grow
• stop expressing MHC I and cannot display tumor Ag
  to CD8 cells
• NK cells destroy MHC I negative cells may be
  mechanism to remove these tumors
• other tumors may make transforming growth factor
  B that suppress immune response

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Immune Evasion
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Immunologic Approaches to Cancer Therapy

• Main goal produce anti-tumor effectors (Ab and
  T-cells)
• immunize patients against their tumors
• stimulate patients own anti-tumor immune response
• Today, tumors can be treated with chemo and
  radiation
• both are harmful to non-cancerous cells

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Early Studies

• Used passive immunization by giving immune
  effectors
• give Ab and often it is coupled to toxin to kill
  cell
• Ab causes phagocytosis or Complement activation
• Ab delivers the toxin to the cell
• HER2/neu is an oncogene over-expressed in some
  breast cancers approved for use
• Use Ab to CD20 on B-cells to treat B-cell tumors
  in combo with chemo CD20 not on stem cells so
  can regenerate B-cells after therapy is complete
• T-cells harvested, expanded in vitro and given
  back to patient Adoptive cellular immunotherapy
  for metastatic tumors varying results

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New Strategies

• Boost hosts own immune responses against tumors
• vaccinate patients with own tumor cells or tumor
  Ag reason to define tumor Ag
• administer as recombinant protein with adjuvant
• grow dendritic cells, expose to tumor cells and
  tumor Ag used as vaccine and hope to cause CTL
  generation
• plasmid with cDNA encoding a tumor Ag expressed
  in host cells make protein and induce specific
  T-cells

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Generate Patient Specific Immune Response

• Let patient generate own tumor-specific immune
  response and design therapies to optimize these
  responses
• treat with cytokines to stimulate immune response
  IL-2 serious toxicity issues
• cytokine gene placed in tumor cell and vaccinate
  with, enhance T-cell response
• express B-7 in tumor cells and use as vaccine
• block inhibitory T-cell CTLA-4 (shuts of T-cell)
• in animal models see a strong anti-tumor response
  against transplanted tumors

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Immune Response Against Transplants

• Transplant rejection is from inflammatory
  response that damages tissue
• Immunologic response
• specific
• memory
• mediated by lymphocytes
• Rejection studies done with mice all one type
  inbred
• Inherited genes with products expresses in all
  tissue

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Terminology

• Donor provides the graft
• Recipient or host getting the transplant
• Syngeneic grafts between identical animals
• Allogeneic grafts from different animals in
  same species allograft
• Xenogeneic grafts between different species
  xenograft
• Ag of regection alloAg or xenoAg
• Ab and T-cell response alloreactive or
  xenoreactive

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Transplant Ag

• Ag of allografts that serve as targets of
  rejection are proteins encoded in the MHC
• human genes are HLA (human leukocyte Ag)
• MHC display peptide Ag for T cells
• 6 MHC I alleles (HLA-A, -B and -C from both
  parents)
• at least 6 MHC II alleles (HLA-DR, -DQ and -DP
  from both parents)
• ?270 alleles for HLA-A and -B alone, bound to
  apprear foreign to others, except identical twins
• HLA-C and -DP are not very polymorphic and play a
  minor role
• MHC on 2nd individuals cells create a strong
  immunological response

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Allogeneic MHC

• Allogeneic MHC with peptide from allogeneic cells
  look like self-MHC with bound foreign peptide
• immunologic cross-reaction
• Clones of T-cell specific for different foreign
  peptides to same self-MHC molecule may
  cross-react with any one allogenic MHC molecule
  so long as allogeneic MHC molecule resembles
  self-MHC and foreign peptide

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Cross-Reaction
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Minor Histocompatibility Ag

• Non-MHC Ag that induce rejection are called minor
  histocompatibility Ag
• allelic forms of normal cellular proteins that
  differ between donor and host
• not as strong as MHC
• important in blood transfusions and bone marrow
  transplants

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Immune Response Against Transplants

• T-cells in recipient may recognize donor alloAg
  in different ways depends on what cells in the
  graft are displaying these alloAg
• T-cells may recognize allogeneic MHC in graft
  displayed on professional APC or graft alloAg may
  be processed and presented by hosts professional
  APC

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Direct Allorecognition

• T-cells activated when T-cell of recipient
  recognizes donor allogeneic MHC on graft
• direct allorecognition
• May be acute rejection pathway

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Indirect Allorecognition

• Happens only when graft has donor-derived
  professional APCs (dendritic cells) that make
  alloreactive T-cells that recognize and attack
  graft OR
• Graft cells ingested by recipient professional
  APC and alloAg presented on self-MHC

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Allorecognition

• Indirect allorecognition is similar to
  cross-presentation in tumor cells
• Professional APC also have costimulator molecules
  to stimulate helper T-cells and alloreactive CTLs
• CTLs come from the indirect path specific for
  AlloAg on self-MHC not sure how CTLs recognize
  allogeneic MHC molecules of graft
• may be because CD4 T-cells secrete cytokines and
  initiate delayed type hypersensitivity

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Mixed Lymphocyte Reaction

• in vitro model of T-cell recognition of alloAg
• T-cells of first person culktured with leukocytes
  of 2nd person and response of T-cells assayed
• magnitude of T-cell response is proportional to
  the extent of MHC differences rough predictor
  of outcome of grafts between these individuals

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Immune Mechanisms of Graft Rejection

• 3 classes of graft rejection based on clinical
  and pathological features
• hyperacute
• acute
• chronic

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Hyperacute Rejection

• Within minutes of transplant not very common
• Thrombosis of graft vessels, ischemic necrosis
• Mediated by Ab to Ag on graft endothelial cells
  probably from prior transfusion
• Activates complement and clotting system

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Acute Rejection

• Within days to weeks after transplant reason
  for early graft failure
• Mainly T-cell mediated against alloAg in graft
• against graft cells or in graft vessels
  vascular damage
• Ab interaction in vascular component
• Immunosupression therapy to prevent and reduce
  acute T-cll medicated rejection

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Chronic Rejection

• Occurs over months to years progressive loss of
  graft function
• Manifests as fibrosis of graft, narroeing of
  graft vessels graft arteriosclerosis
• T-cells thought to be responsible with cytokine
• stimulation of proliferation of fibroblast and
  vascular smooth muscle cells
• Becoming principle cause of graft rejection

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Prevention and Treatment

• Immunosuppression designed mainly to inhibit
  T-cell activation and effector function
• Cyclosporine is the most useful immunosuppressent
  
• blocks T-cell phosphatase that activates
  transcription factor NFAT
• others used in addition or instead of
• causes non-specific immunosupression patients
  are susceptible to intracellular microbes, also
  oncogenic tumor viruses
• rarely causes tumors

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Additional Pre-treatment

• HLA alleles matched between donor and recipient
  helped to minimize rejection before cyclosporine
• Immunologist try to induce tolerance to graft
  alloAg without interfering with other immune
  system function
• Organ transplant shortage
• xenotransplantation possible source but cause
  hyperacute rejection, do not require previous
  exposure, also subject to acute rejection

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Transplantation of RBC and BM Cells

• RBC transfusion is the oldest method of
  transplant must match antigens on RBC and Ab in
  serum and donor cells
• if mis-matched could cause severe transfusion
  reaction
• Bone marrow transplant used in hematopoetic
  defects or restore bone marrow caused by chemo or
  irradiation
• requires careful HLA matching
• mature T-cells in graft can attack recipient
  tissue Graft vs Host defense
• recipients often severely immune-deficient while
  immune system is reconstituted