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7 immunology-csbrp
1. Organ transplantation is used to treat organs that are severely malformed or damaged, with rejection by the host immune system being a major obstacle. 2. There are different types of transplants based on how similar the donor and recipient are genetically, ranging from autographs within an individual to xenographs between species. 3. The most common form of allograft is blood transfusion.
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7 immunology-csbrp
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- 2. Organ transplantation isthe Rx of choice when an organ ….. - has severe congenital malformation - is irreversibly damaged by some disease process Main obstacle is rejection of transplanted organ by the host Transplantation Immunology APR-2015-CSBRP
- 3. Transplantation - terminologyTransplantation- terminology • Autograft – Donor & recipient is same individual • Isograft - Donor & recipient is same genotype • Allograft - Donor & recipient is of same species but different genotype • Xenograft – Donor is different species from that of recipient Skin , kidney, BM, heart, lung, liver, cornea APR-2015-CSBRP
- 4. Transplant rejectionTransplant rejection •Any two individuals express 2 different HLA protein • Rejection is a complex process in which both cell mediated immunity & circulating Ab play a role • T cell mediated reaction – CD4 + helper cells – mediate Delayed hypersensitivity reaction – CD8+ CTLS – mediate graft cell destruction APR-2015-CSBRP
- 5. Which is themost common Allograft procedure in medicine? Blood TransfusionBlood Transfusion APR-2015-CSBRP
- 6. Histocompatibility Antigens (HLA) Chromosome #6 Identity of SELF APR-2015-CSBRP
- 7. Histo-compatibility AntigenHisto-compatibility Antigen •Base on structure, distribution and function of MHC gene products • Class I MHC antigens have loci as HLA- A, HLA – B and HLA – C • Class II MHC antigens have single locus HLA – D . It has 3 subregions – HLA- DP, HLA-DQ and HLA- DR • Class III genes - Complement APR-2015-CSBRP
- 8. MHC region onChr# 6 APR-2015-CSBRP
- 9. Class I MHCantigensClass I MHC antigens • Expressed on all nucleated cells & platelet • It binds to peptides that are derived from proteins such as viral antigens • Cells process the antigen and transported to cell surface for presentation to CD8 cytotoxic T lymphocytes APR-2015-CSBRP
- 10. Figure 6-10 Antigen processingand recognition. The sequence of events in the processing of a cytoplasmic protein antigen and its display by class I MHC molecules are shown at the top. The recognition of this MHC-displayed peptide by a CD8+ T cell is shown at the bottom. APR-2015-CSBRP
- 11. Class II MHCantigensClass II MHC antigens • Present only on APC – Macrophages, Dendritic cells & B cells • It binds to exogenous antigens (microbes, soluble proteins) that are first internalised and processed in endosomes / lysosomes • Peptide - MHC complex is transported to the cell surface, where it is recognized by CD4 helper T cells APR-2015-CSBRP
- 12. The T-cell receptor(TCR) complex: B, Recognition of MHC- associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR- associated ζ chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules). APR-2015-CSBRP
- 13. HLA systemHLA system •Five HLA genes • Ten possible loci • Large # of different determinants (A-17, B-27, C-6, D-11 & DRw-8) • Codominants • 30million unique combinations (where there is no significant interbreeding) APR-2015-CSBRP
- 14. HLA systemHLA system However,this huge number (1:30millions) is reduced to thousands by naturally occuring gene linkages called “Linkage disequilibirum” APR-2015-CSBRP
- 15. Linkage disequilibriumLinkage disequilibrium •Population studies have shown certain combinations of – A&B – A&C – B&D occur together more commonly than expected from random inheritance Eg: Caucasians have HLA-A1, B8 and DRw3 profile • Cross-over between the HLA-A and D loci rarely occurs (<1% of births) APR-2015-CSBRP
- 16. Choice of DonorChoiceof Donor • Close HLA match is required to…. Reduce the chances of rejection and Reduce the dosage of immunosuppressives • ABO & P blood group compatible APR-2015-CSBRP
- 17. Choice of Donor- LivingChoice of Donor - Living • Identical twin – best • Compatible HLA-A & B – next best APR-2015-CSBRP
- 18. Choice of Donor- CadaverChoice of Donor - Cadaver • Compatibility to 3 to 4 antigens of A&B improves survival of the graft • HLA-B match is very important • HLA-C match has very limited role • HLA-DR compatibility is required but, it’s difficult to comply with APR-2015-CSBRP
- 19. Other factors influencingallograft survivalOther factors influencing allograft survival • History of multiple transfusions - decreases • Previous pregancies – decreases • Pre-graft blood transfusion – improves survival • Immunosuppressive Rx - improves APR-2015-CSBRP
- 20. Immunological rejection ofallograftsImmunological rejection of allografts There are THREE types of allograft rejection 1. Hyperacute rejection 2. Acute rejection 3. Chronic rejection APR-2015-CSBRP
- 21. Immunological rejection ofallograftsImmunological rejection of allografts There are THREE types of allograft rejection 1. Hyperacute rejection: Occurs immediately after establishing circulation (minutes to hours) Due to preformed cytotoxic Abs Result: Vascular injury & Thrombosis Organ becomes cyanotic, mottled, and flaccid Tissue infarction APR-2015-CSBRP
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- 23. Immunological rejection ofallograftsImmunological rejection of allografts There are THREE types of allograft rejection 1. Hyperacute rejection 2. Acute rejection Occurs within 30-90 days of transplant DTH / IgG mediated NK-cell cytotoxicity Vasculature is normal (except endothelitis) Intense mononuclear infiltrate in the organ Rapid fall in organ function APR-2015-CSBRP
- 24. Immunological rejection ofallograftsImmunological rejection of allografts 2 - Acute rejection APR-2015-CSBRP
- 25. Immunological rejection ofallograftsImmunological rejection of allografts There are THREE types of allograft rejection 1. Hyperacute rejection 2. Acute rejection 3. Chronic rejection After months or years Humoral / CMI mediated damage Progressive loss of function Sclerosis APR-2015-CSBRP
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- 27. Methods of IncreasingGraftMethods of Increasing Graft SurvivalSurvival • HLA matching • ABO & P matching • Immunosuppressive Rx • Induction of donor-specific tolerance in host T cells APR-2015-CSBRP
- 28. The T-cell receptor(TCR) complex: B, Recognition of MHC- associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR- associated ζ chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules). APR-2015-CSBRP
- 29. HLA matching isnot done in the case of: Heart, Lung, Pancreas, Liver transplants Rejection reaction against liver transplants is not as vigorous as might be expected from the degree of HLA disparity Exact mechanisms not known Transplantation of Other Solid OrgansTransplantation of Other Solid Organs APR-2015-CSBRP
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- 31. GVHDGVHD • Graft mountsan attack on the host tissue • Immunodeficiency is a common denominator • May occur in two situations 1-BM transplantation 2-Inbred population APR-2015-CSBRP
- 32. GVHDGVHD Manifestaions: • Skin rashwith desquamation • Mucositis • Hepatitis APR-2015-CSBRP
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- 39. Oral lichenoid mucosalreaction and periodontal disease, occurring as part of graft-versus-host disease APR-2015-CSBRP
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- 41. Rash involving Palms& Soles • Meningococcemia • Reiter’s syndrome • Kawasaki, Measles, or Toxic Shock Syndrome • Hand, Foot, and Mouth Disease • Mercury poisoning in children • Bacterial endocarditis • Tylosis • Rocky Mountain Spotted Fever • GVHD rash • Steven Johnson syndrome • Secondary and Congenital Syphilis • Acral lentiginous melanoma • Typhus APR-2015-CSBRP
- 42. Hand Foot MouthDisease APR-2015-CSBRP
- 43. Rocky Mountain spottedfever APR-2015-CSBRP
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Editor's Notes
- #13 Figure 6-4 The T-cell receptor (TCR) complex. A, Schematic illustration of TCRα and TCRβ chains linked to the CD3 complex. B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ (Zeta) chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules). έ = Epslon
- #16 i.e. A&D go together. Therefore siblings who are identical for HLA-A&B loci are usually identical for HLA-D as well, something found in only 10% of unrelated donors.
- #17 Complications with immunosuppressive therapy: Fatal infections, DM, Cataract and Malignancies.
- #18 In a given family of siblings there is 1in4 chances for identicality (A&B) and 1in2 chances of having one identical allele (haplotype).
- #19 In a given family of siblings there is 1in4 chances for identicality (A&B) and 1in2 chances of having one identical allele (haplotype).
- #22 Occurs immediately after establishing circulation (minutes to hours) Due to preformed cytotoxic Abs against HLA or ABO Ags Result: Vascular injury & Thrombosis Organ becomes cyanotic, mottled, and flaccid Tissue infarction
- #23 Kidney Transplantation Graft Rejection
- #25 Figure 6-24 Acute cellular rejection of a renal allograft. A, An intense mononuclear cell infiltrate occupies the space between the tubules. B, T cells (stained brown by the immunoperoxidase technique) are abundant in the interstitium and infiltrating a tubule. (Courtesy of Dr. Robert Colvin, Department of Pathology, Massachusetts General Hospital, Boston, MA.) In addition to causing tubular damage, CD8+ cells may also injure vascular endothelial cells, causing a so-called endothelitis. This form of cell-mediated vascular damage is limited to the endothelium and is distinct from the antibody-mediated vasculitis described later. The affected vessels have swollen endothelial cells, and at places the lymphocytes can be seen between the endothelium and the vessel wall. The recognition of cellular rejection is important because, in the absence of an accompanying arteritis, patients promptly respond to immunosuppressive therapy. Cyclosporine, a widely used immunosuppressive drug, is also nephrotoxic, and hence the histologic changes resulting from cyclosporine may be superimposed.
- #27 Figure 6-26 Chronic rejection in a kidney allograft. A, Changes in the kidney in chronic rejection. B, Graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue in the vessel intima. (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women&apos;s Hospital and Harvard Medical School, Boston, MA.) Chronic rejection is dominated by vascular changes, interstitial fibrosis, and tubular atrophy with loss of renal parenchyma ( Fig. 6-26 ). The vascular changes consist of dense, obliterative intimal fibrosis, principally in the cortical arteries. These vascular lesions result in renal ischemia, manifested by glomerular loss, interstitial fibrosis and tubular atrophy, and shrinkage of the renal parenchyma. The glomeruli may show duplication of basement membranes; this appearance is sometimes called chronic transplant glomerulopathy. Chronically rejecting kidneys usually have interstitial mononuclear cell infiltrates containing large numbers of plasma cells and numerous eosinophils.
- #28 Although immunosuppression has produced significant gains in terms of graft survival, immunosuppressive therapy carries its own risks. The price paid in the form of increased susceptibility to opportunistic fungal, viral, and other infections is not small. These patients are also at increased risk for developing EBV-induced lymphomas, human papillomavirus-induced squamous cell carcinomas, and Kaposi sarcoma ( Chapter 11 ). To circumvent the untoward effects of immunosuppression, much effort is being devoted to induce donor-specific tolerance in host T cells.[33] One strategy being pursued in experimental animals is to prevent host T cells from receiving costimulatory signals from dendritic cells during the initial phase of sensitization. This can be accomplished by interrupting the interaction between the B7 molecules on the dendritic cells of the graft donor with the CD28 receptors on host T cells, as, for example, by administration of proteins that bind to B7 costimulators. This, as discussed earlier, interrupts the second signal for T-cell activation and renders the T cells anergic or induces their apoptosis. Antibodies that block CD40 ligand are also being tried; they presumably work by inhibiting humoral immune responses and CTL generation. In addition, giving donor cells to graft recipients may prevent reactions to the graft, perhaps because the donor inoculum contains cells, such as immature dendritic cells, that induce tolerance to the donor alloantigens. This approach may result in long-term mixed chimerism, in which the recipient lives with the injected donor cells. Such approaches are being tried in patients.
- #29 Figure 6-4 The T-cell receptor (TCR) complex. A, Schematic illustration of TCRα and TCRβ chains linked to the CD3 complex. B, Recognition of MHC-associated peptide displayed on an antigen-presenting cell (top) by the TCR. Note that the TCR-associated ζ (Zeta) chains and CD3 complex deliver signals (signal 1) upon antigen recognition, and CD28 delivers signals (signal 2) upon recognition of costimulators (B7 molecules). έ = Epslon
- #30 Although immunosuppression has produced significant gains in terms of graft survival, immunosuppressive therapy carries its own risks. The price paid in the form of increased susceptibility to opportunistic fungal, viral, and other infections is not small. These patients are also at increased risk for developing EBV-induced lymphomas, human papillomavirus-induced squamous cell carcinomas, and Kaposi sarcoma ( Chapter 11 ). To circumvent the untoward effects of immunosuppression, much effort is being devoted to induce donor-specific tolerance in host T cells.[33] One strategy being pursued in experimental animals is to prevent host T cells from receiving costimulatory signals from dendritic cells during the initial phase of sensitization. This can be accomplished by interrupting the interaction between the B7 molecules on the dendritic cells of the graft donor with the CD28 receptors on host T cells, as, for example, by administration of proteins that bind to B7 costimulators. This, as discussed earlier, interrupts the second signal for T-cell activation and renders the T cells anergic or induces their apoptosis. Antibodies that block CD40 ligand are also being tried; they presumably work by inhibiting humoral immune responses and CTL generation. In addition, giving donor cells to graft recipients may prevent reactions to the graft, perhaps because the donor inoculum contains cells, such as immature dendritic cells, that induce tolerance to the donor alloantigens. This approach may result in long-term mixed chimerism, in which the recipient lives with the injected donor cells. Such approaches are being tried in patients.
- #32 Acute GVH disease occurs within days to weeks after allogeneic bone marrow transplantation. Although any organ may be affected, the major clinical manifestations result from involvement of the immune system and epithelia of the skin, liver, and intestines. Involvement of skin in GVH disease is manifested by a generalized rash leading to desquamation in severe cases. Destruction of small bile ducts gives rise to jaundice, and mucosal ulceration of the gut results in bloody diarrhea. Despite considerable tissue damage, the affected tissues are not heavily infiltrated by lymphocytes. It is believed that in addition to direct cytotoxicity by CD8+ T cells, considerable damage is inflicted by cytokines released by the sensitized donor T cells.
- #33 Acute GVH disease occurs within days to weeks after allogeneic bone marrow transplantation. Although any organ may be affected, the major clinical manifestations result from involvement of the immune system and epithelia of the skin, liver, and intestines. Involvement of skin in GVH disease is manifested by a generalized rash leading to desquamation in severe cases. Destruction of small bile ducts gives rise to jaundice, and mucosal ulceration of the gut results in bloody diarrhea. Despite considerable tissue damage, the affected tissues are not heavily infiltrated by lymphocytes. It is believed that in addition to direct cytotoxicity by CD8+ T cells, considerable damage is inflicted by cytokines released by the sensitized donor T cells.
- #34 Early, chronic graft-versus-host reaction with widespread, almost confluent hyperpigmented lichenoid papules and toxic epidermal necrosis-like appearance on knee.
- #35 Late, chronic graft-versus -host reaction with hyperpigmented sclerotic plaques on the back.
- #37 Acute graft-versus-host reaction with vivid palmar erythema
- #38 Acute graft-versus-host reaction with vivid palmar erythema
- #39 Graft-versus-host reaction with early, chronic, diffuse, widespread lichenoid changes of lips
- #40 Oral lichenoid mucosal reaction and periodontal disease, occurring as part of graft-versus-host disease
- #41 Graft-versus-host reaction; acute basal cell hydropic degeneration with interepidermal necrotic keratinocytes
- #42 Keratoderma blenorrhagica (Reiter’s syndrome) Secondary and Congenital Syphilis with it’s characteristic Copper colored rash
- #43 Cocksakie A virus
- #45 Coppery rash
- #46 www.aafp.org/afp/2010/0315/p735.html Am Fam Physician. 2010 Mar 15;81(6):735-39 The generalized rash: part-II. Diagnostic approach John W. Ely.