Transplantation Lecture 11
Preventing Graph rejection Reduce graft immunogenicity by selecting most compatible graft: •Class __ and class ___ MHC proteins expression can be determined by ________ and _________ techniques. •Although two siblings may be matched at all their MHC proteins → some rejection due to __________ histocompatibility antigen differences. -E.g. minor histocompatibility proteins encoded by _ chromosome cause a _______ anti-male minor histocompatibility response. No male anti-female rejection as both sexes have __ chromosome.
Reduce graft immunogenicity by selecting most compatible graft: •Class I and class II MHC proteins expression can be determined by serological and molecular techniques. •Although two siblings may be matched at all their MHC proteins → some rejection due to minor histocompatibility antigen differences. -E.g. minor histocompatibility proteins encoded by Y chromosome cause a female anti-male minor histocompatibility response. No male anti-female rejection as both sexes have X chromosome.
other tissue/organs for transplants Relatively high success rates with heart transplantation: •_______________ vascular injury → high incidence of new ____________ disease in coronary arteries Pancreas transplantation performed to treat ________________: •Newer approach is to transplant insulin-producing _____ cells alone •Limited success to date
Relatively high success rates with heart transplantation: •Antibody-mediated vascular injury → high incidence of new atherosclerotic disease in coronary arteries Pancreas transplantation performed to treat diabetes mellitus: •Newer approach is to transplant insulin-producing islet cells alone •Limited success to date
Acute Rejection for Graft rejection Takes place within __ month of transplantation. Two basic types: •______ ________ ______: Antibody and _______ - ________ lysis of graft tissue → ________ of the blood vessel walls •_______ _______ _________: _______-________ lysis of graft tissue by _____, ___ cells, and/or _____________ Treated with ↑ ___________, e.g. high dose steroid therapy or anti-T cell antibodies.
Acute Rejection for Graft rejection Takes place within 1 month of transplantation. Two basic types: •Acute humoral rejection: Antibody and complement-mediated lysis of graft tissue → necrosis of the blood vessel walls •Acute cellular rejection: Cell-mediated lysis of graft tissue by CTL's, NK cells, and/or macrophages Treated with ↑ immunosuppression, e.g. high dose steroid therapy or anti-T cell antibodies.
Alloreactivity Recognition of foreign MHC proteins by the TCR due to polymorphic amino acids of foreign MHC proteins mimicking conformation of both _______and ___________: •Same TCR can recognize self ____ + ______ peptide conformations as well as ____ MHC proteins •20% of T cells can be alloreactive toward a set of foreign MHC proteins, therefore alloreactivity is felt to be the most important mechanism for T-helper cell activation.
Alloreactivity Recognition of foreign MHC proteins by the TCR due to polymorphic amino acids of foreign MHC proteins mimicking conformation of both self MHC and foreign peptide: •Same TCR can recognize self MHC + foreign peptide conformations as well as foreign MHC proteins •20% of T cells can be alloreactive toward a set of foreign MHC proteins, therefore alloreactivity is felt to be the most important mechanism for T-helper cell activation.
Alloreactivity T cells need _______ + self ____ proteins and allografts express foreign MHC proteins, therefore how do they activate T cells? Recipient APC's could present foreign ____ peptides in conjunction with self class ___ MHC proteins to activate _________ cells: •Does occur, but cannot be the primary mechanism for T-helper cell activation, since CTL's could not lyse the foreign MHC class I-bearing graft cells (since they couldn't recognize non-self class I MHC).
Alloreactivity T cells need antigen + self MHC proteins and allografts express foreign MHC proteins, therefore how do they activate T cells? Recipient APC's could present foreign MHC peptides in conjunction with self class II MHC proteins to activate T-helper cells: •Does occur, but cannot be the primary mechanism for T-helper cell activation, since CTL's could not lyse the foreign MHC class I-bearing graft cells (since they couldn't recognize non-self class I MHC).
An _________ graft : •Transplant between two genetically ___________individuals of the same ________ •Most common form of transplant A __________ graft, or __________, is a transplant between members of two ____________ species.
An allogeneic graft: •Transplant between two genetically dissimilar individuals of the same species •Most common form of transplant A xenogeneic graft, or xenograft, is a transplant between members of two different species.
GVHD for bone marrow transplant _______ monoclonal antibodies (with Complement) → ___ incidence of GVHD, but reduces chance of ________ Graft-versus-leukemia effect = helps prevent ______ of cancer because the GVHD reaction removes ______ _________ _________. Fine line between allowing no GVHD and risking cancer recurrence and much GVHD, which is potentially life-threatening.
Anti-CD3 monoclonal antibodies (with Complement) → ↓ incidence of GVHD, but reduces chance of engraftment Graft-versus-leukemia effect = helps prevent recurrence of cancer because the GVHD reaction removes minimal residual disease. Fine line between allowing no GVHD and risking cancer recurrence and much GVHD, which is potentially life-threatening.
what does autologous and sygeneic mean?
Autologous graft - a graft transplanted from an individual to the same individual. Example = bone marrow or blood harvested and saved for future use. Syngeneic grafts, or syngraft, is a transplant between two genetically identical individuals (i.e. identical twins).
Bone Marrow Donation Autologous peripheral blood _____ cell transplantation: •_______ administration → ________ bone marrow stem cells to blood •_____________, followed by sorting by flow cytometry •Less invasive and less chance of "minimal residual disease"
Autologous peripheral blood stem cell transplantation: •(Granulocyte colony stimulating factor ) G-CSF administration → mobilizes bone marrow stem cells to blood •Leukapheresis, followed by sorting by flow cytometry •Less invasive and less chance of "minimal residual disease"
Chronic rejection May occur ______ or _________ after transplantation: •Mechanism unknown: May involve ________-_________ injury to the graft vasculature or _____________ reactions •________ and _________ of collagen are characteristic with accelerated ____________ resulting in vascular occlusion •Unresponsive to ↑ _________________
Chronic rejection May occur months or years after transplantation: •Mechanism unknown: May involve antibody-mediated injury to the graft vasculature or delayed-type hypersensitivity (DTH) reactions •Fibrosis and deposition of collagen are characteristic with accelerated arteriosclerosis resulting in vascular occlusion •Unresponsive to ↑ immunosuppression
Graft-vs-host disease for bone marrow transplant Differentiates bone marrow transplantation from all other types: •Acute GVHD → quickly following bone marrow transplantation and involves _______ cell necrosis of the ____, ____ and __ tract. Fatal in some severe cases. •Chronic GVHD → ______ in organs causing dysfunction. Fatal if severely affects critical organs.
Differentiates bone marrow transplantation from all other types: •Acute GVHD → quickly following bone marrow transplantation and involves epithelial cell necrosis of the skin, liver and GI tract. Fatal in some severe cases. •Chronic GVHD → fibrosis in organs causing dysfunction. Fatal if severely affects critical organs.
Hyperacute Rejection for Graft rejection Takes place within _______ of attaching the graft to the recipient's blood supply: •Mediated by pre-existing _________ •E.g.: Anti-ABO blood group antibodies •Essentially __________, but uncommon
Hyperacute Rejection Takes place within minutes of attaching the graft to the recipient's blood supply: •Mediated by pre-existing antibodies •E.g.: Anti-ABO blood group antibodies •Essentially untreatable, but uncommon
Immunologically privileged sites Antigens at these sites can be targeted: •___________ __________ → one eye is damaged by trauma and autoimmune response to eye proteins threatens the undamaged eye •________________ therapy required to prevent destruction of undamaged eye. Removal of damaged eye may be required.
Immunologically privileged sites Antigens at these sites can be targeted: •Sympathetic ophthalmia → one eye is damaged by trauma and autoimmune response to eye proteins threatens the undamaged eye •Immunosuppressive therapy required to prevent destruction of undamaged eye. Removal of damaged eye may be required.
Immunologically privileged sites Locations where allogeneic transplant placed without risk of rejection: •Anterior chamber of eye, cornea, testes, brain •Accounts for near universal success of cornea transplants Mechanisms of "privilege": •Extracellular fluid that bathes these tissues doesn't leave through the conventional lymphatic system •TGF-β, an inhibitory cytokine, produced at these sites •Fas ligand → reacts with Fas on lymphocytes to induce apoptosis
Immunologically privileged sites Locations where allogeneic transplant placed without risk of rejection: •Anterior chamber of eye, cornea, testes, brain •Accounts for near universal success of cornea transplants Mechanisms of "privilege": •Extracellular fluid that bathes these tissues doesn't leave through the conventional lymphatic system •TGF-β, an inhibitory cytokine, produced at these sites •Fas ligand → reacts with Fas on lymphocytes to induce apoptosis
preventing rejection Immunosuppression: •___________ → lyse immature _________, block release of cytokines from __________ and inhibit __________ migration •_____________ = drug of choice for immunosuppression → inhibits IL-__ and ____ gene expression, preventing activation of _____________________: •Not as effective at inhibiting ___ immune responses, compared to 1o •Nephrotoxic •Anti-___________ globulin = horse serum → kills wanted and unwanted _________, but can reverse ________ graft rejection: •Serum sickness = common side effect Infections and malignancies (e.g. B cell lymphomas, squamous cell carcinoma, and Kaposi's sarcoma) can develop
Immunosuppression: •Corticosteroids → lyse immature thymocytes, block release of cytokines from macrophages and inhibit leukocyte migration •Cyclosporine = drug of choice for immunosuppression → inhibits IL-2 and IFN-g gene expression, preventing activation of cell-mediated immunity: •Not as effective at inhibiting 2o immune responses, compared to 1o •Nephrotoxic •Anti-lymphocyte globulin = horse serum → kills wanted and unwanted lymphocytes, but can reverse acute graft rejection: •Serum sickness = common side effect Infections and malignancies (e.g. B cell lymphomas, squamous cell carcinoma, and Kaposi's sarcoma) can develop
Mechanisms to prevent immune response against fetal antigens: •Trophoblast cells don't express ________ MHC proteins. In addition, _____, an MHC class __ like protein, keeps ___ cells from becoming activated by the trophoblast cells that express __ MHC proteins. •Trophoblast cells may secrete inhibitory cytokines such as ______. •Tryptophan is broken down at the fetal-maternal interface by the enzyme indolamine 2,3-dioxygenase. Tryptophan-starved T lymphocytes react poorly to antigen.
Mechanisms to prevent immune response against fetal antigens: •Trophoblast cells don't express paternal MHC proteins. In addition, HLA-G, an MHC class I-like protein, keeps NK cells from becoming activated by the trophoblast cells that express no MHC proteins. •Trophoblast cells may secrete inhibitory cytokines such as TGF-b. •Tryptophan is broken down at the fetal-maternal interface by the enzyme indolamine 2,3-dioxygenase. Tryptophan-starved T lymphocytes react poorly to antigen.
_________ transplant - graft placed in its normal anatomic location ___________ transplant - placed in an anatomically different site •E.g. heart bypass surgery using arteries that originated from a leg that were transplanted to the heart
Orthotopic transplant - graft placed in its normal anatomic location Heterotopic transplant - placed in an anatomically different site •E.g. heart bypass surgery using arteries that originated from a leg that were transplanted to the heart
other organs and tissues Skin grafting - treatment of burn victims. ________ grafts are most successful. ________ grafts using frozen deposits from a tissue bank can be used for a short period with _____________. 10,000 kidney transplants are performed annually. Cadaveric donors provide most kidneys, but living, unrelated donors are ↑. Liver transplantation - transplanted even in the face of pre-existing __________. Carries large numbers of donor ____________ → ↑ risk of GVHD. Liver can ___________, so ↑ living, related donors.
Skin grafting - treatment of burn victims. Autologous grafts are most successful. Allogeneic grafts using frozen deposits from a tissue bank can be used for a short period with immunosuppression. 10,000 kidney transplants are performed annually. Cadaveric donors provide most kidneys, but living, unrelated donors are ↑. Liver transplantation - transplanted even in the face of pre-existing antibodies. Carries large numbers of donor lymphocytes → ↑ risk of GVHD. Liver can regenerate, so ↑ living, related donors.
Transplantation Laws 1. Transplants between _________ _________ are never rejected. 2. Transplants between genetically dissimilar individuals are almost ________ ________ (i.e. without __________________). 3. Grafts derived from children will be rejected by either _____. Children would express antigens that either parent sees as __________.
Transplantation Laws 1. Transplants between identical twins are never rejected. 2. Transplants between genetically dissimilar individuals are almost always rejected (i.e. without immunosuppression). 3. Grafts derived from children will be rejected by either parent. Children would express antigens that either parent sees as foreign.
Transplantation Laws Class __ and class ___ MHC proteins are perceived as ______. "Minor histocompatibility" antigens may also play a role (not discussed). Perceived as foreign because: •Expression = ________ → all express particular set of "____" MHC •Education of _________ → other MHC proteins perceived as foreign •Probability that two random individuals express same ______ proteins is extremely small
Transplantation Laws Class I and class II MHC proteins are perceived as foreign. "Minor histocompatibility" antigens may also play a role (not discussed). Perceived as foreign because: •Expression = polymorphic → all express particular set of "self" MHC •Education of thymocytes → other MHC proteins perceived as foreign •Probability that two random individuals express same MHC proteins is extremely small
General principle for Bone marrow transplantation Transplantation of donor hematopoietic stem cells can repopulate recipient's bone marrow. Used to treat certain malignancies, such as leukemias, and immunodeficiency states: •Cancer and some immunodeficiency patients undergo radiation and/or chemotherapy to ablate bone marrow. •Donor bone marrow is administered i.v. with "homing" to bone marrow. •Unless autologous or syngeneic bone marrow is used, graft-versus-host disease (GVHD) may develop.
Transplantation of donor hematopoietic stem cells can repopulate recipient's bone marrow. Used to treat certain malignancies, such as leukemias, and immunodeficiency states: •Cancer and some immunodeficiency patients undergo radiation and/or chemotherapy to ablate bone marrow. •Donor bone marrow is administered i.v. with "homing" to bone marrow. •Unless autologous or syngeneic bone marrow is used, graft-versus-host disease (GVHD) may develop.
Types of Rejection Rejection caused by specific immune reaction to transplanted tissue follows similar course as ___ and ___ immune responses (called "______" and "_______" rejection). ____ ----- rejection: Skin grafts transplanted between genetically non-identical mice rejected in __-____ days (similar to 1o immune response) __________ rejection: When skin graft is transplanted again → graft rejected in ___-___ days (as in a 2o immune response)
Types of Rejection Rejection caused by specific immune reaction to transplanted tissue follows similar course as 1o and 2o immune responses (called "first set" and "second set" rejection). First set rejection: Skin grafts transplanted between genetically non-identical mice rejected in 7-10 days (similar to 1o immune response) Second set rejection: When skin graft is transplanted again → graft rejected in 2-3 days (as in a 2o immune response)
alloreactivity Activation events: (see next slide also) •Step 1: _______ (using donor dendritic cells) and ______ (using recipient dendritic cells) presentation of alloantigens stimulates ______ alloreactive T cells (from the recipient) to become activated. •Step 2: ________ ______ T helper cells provide IL-__ and _____ to alloreactive ______ T cells to produce CTL's that can lyse graft cells, alloreactive B cells to produce anti-graft antibodies.
alloreactivity Activation events: (see next slide also) •Step 1: Direct (using donor dendritic cells) and indirect (using recipient dendritic cells) presentation of alloantigens stimulates CD4+ alloreactive T cells (from the recipient) to become activated. •Step 2: Alloreactive CD4+ T helper cells provide IL-2 and IFN-g to alloreactive CD8+ T cells to produce CTL's that can lyse graft cells, alloreactive B cells to produce anti-graft antibodies.
Maternal-fetal interaction mimics ___________ and graft rejection ex. the fetus is a naturally occurring __________
alloreactivity/ allograft
Depletion of passenger _________ from graft can eliminate or delay graft rejections. This prevent _______ antigen presentation
leukocytes / direct
