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Responses to alloantigens and transplant rejection Immune response against grafted cells tissues, or organs CH15 Ch16 Immune modulators

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Chapter 15 Transplantation of tissues and organs The immune system Third edition Peter Parham (2009)

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Identity of transplantation antigens Type and prevention of immune response in rejection of solid organs Bone marrow transplantation

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Donor

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Autograft Isograft Allograft Xenograft MHC Ag Class I Class II Major histocompatibility complex (MHC) Identity of transplantation antigens

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Hyperacute rejection (within 24h) Acute rejection (first few weeks) Chronic rejection (months - years) Type and prevention of immune response in rejection of solid organs

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Hyperacute rejection C, blood clotting Pre-existing Ab (e.g. Anti-MHC, A/B/O) Repeated blood transfusions Repeated pregnancies Previous graft Immediate graft death

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Hyperacute rejection

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Cell-mediated immunity (CMI) Acute rejection Th1 response Macrophages (Type IV hypersensitivity) CTLs Allogeneic T cells The frequency of T cells specific for any non-self MHC molecules is relatively high Cross reactivity (first few weeks) MHC polymorphism

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Cross reactivity Self High affinity to non-self MHC Ag Affinity High frequency of allogeneic T cells

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Donor DC Acute rejection Anti-CD3

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In vitro mixed lymphocyte reaction (MLR) APC: donorT: recipient Target: donor

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Minor histocompatibility Ag HLA matching Polymorphic Ag (proteins that differ in amino acid sequence between individuals)

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Donor Recipient Donor Two ways of allo-Ag recognition

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Chronic rejection (months - years) FcR Infiltration Fibrosis Atrophy

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Cancer therapy Genetic diseases of blood cells Chemotherapy Repopulation Reconstitution of the patients immune system and also their red cells and platelets Intravenous infusion Bone marrow transplantation

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T cells : thymus MHC restriction Positive selection 17

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Hematopoiesis MHC a MHC b MHC axb APC 18

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Bone marrow-derived APC Thymic non-lymphoid stroma Bone marrow chimera Blood type The more HLA allotypes they share, the better it works

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HLA-haploidentical family members

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Engraftment: Colonization of HSC in the bone of recipient Myeloablative therapy Niche Enrichment

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Graft-versus-host disease (GVHD) Recipient DC Stringent T-cell depletion

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Tissue inflammation Cytokine storm Activation of allogeneic T cells Acute GVHD: First few months Graft-versus-leukemia effect Graft-versus-tumor effect