Immunology Related to Clinical Transplantation

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Microbiology and Immunology
Microbiology and Immunology 2500A/B

Guest Lecture: Immunology Related to Clinical Transplantation 11/26/2012 Objectives  Discuss why transplantation is a desirable goal for chronic organ disease and discuss organ shortage  Discuss basic immunology of all responses, including the role of HLA and T cell interactions  Discuss the major current strategies of immunosuppression and their risks  Discuss how patients are matched to potential donors, including ABO blood grouping, HLA matching  Discuss the clinical presentation, lab findings and differential diagnosis of acute graft dysfunction (including rejection) Kidney Function  Regulates salt and water  Produces hormones  Controls blood pressure  Clears waste products  Maintains acid base balance  Kidney failure: o Functioning at less than 15% o Kidney failure is usually silent, and is caused by many different factors Treatments for Kidney Failure  Dialysis o Hemodialysis  Three times per week  Daily  Nocturnal  Hospital/satellite unit/home o Peritoneal Dialysis  Intermittent  Nocturnal cycler  Home  Transplantation o Deceased donor – most common  Neurological death  Cardiac death o Living donor  Related  Unrelated/emotional  Anonymous  Living donor paired exchange Benefits of Transplantation  Best option for patients with kidney disease who are suitable to receive a transplant  Not a cure – disease is still present  Improved quality of life / life saving o No dialysis o Decreased cardiovascular risk o Increased energy o No diet or fluid restrictions o More normal lifestyle (freedom) Kidney Transplantation: It’s a Good Thing  Transplantation offers patients with end-stage renal disease (ESRD) the greatest potential for increased longevity and enhanced quality of life vs. dialysis  Overall, the 5 year survival rate for patients who received a kidney transplant is 74% vs. 34% for those left on the waitlist and hemodialysis Risks of Kidney Transplantation  Complex surgery  Life-long use of anti-rejection medications to prevent rejection  Side effects of medication o Infections o Cancer (skin, lymphoma) o Diabetes o Bone disease  Rejection  Recurrence of original disease Kidney Transplantation  Own, non-functioning kidney remains  Transplant kidney goes into pelvis Transplant Outcomes: Donor Organ Dependent  All donors carefully evaluated for kidney function and disease transmission o Deceased donor: 8 – 12 years o Living donor: 12 – 20 years  1 year graft survival (North America) o 90% deceased donor kidneys o 95% living donor kidneys  Challenge: Increasing discrepancy between amount of donors and amount of patients in need of a transplantation Definitions  Histocompatibility antigens: antigens on tissues and cells that are the target of rejection when grafter between two genetically different individuals  Major histocompatibility (MHC) antigens: histocompatibility antigens that cause a very strong immune response and are most important in rejection  MHC complex: group of genes on a single chromosome encoding the MHC antigens  HLA (human leukocyte antigens): MHC antigens of man (first detected on leukocytes) Human Leukocyte Antigens  T cell responses are not only necessary, but also sufficient for allograft destruction T Cell Alloreactivity  T-cell recognition of genetically encoded polymorphisms between members of the same species  Principal targets of the immune response to allogeneic tissues are the major histocompatibility complex (MHC) molecules  Recognition of allograft MHC antigen is the primary event that ultimately leads to graft rejection Anatomy of the Allo-Response in Vivo  Donor DC activate the direct pathway of the anti-donor response  Recipient DC presents donor peptides traffic in lymph nodes  Donor DC trafficking to lymph node provide a source of antigen for priming the direct pathway  Recipient DC activate the indirect pathway of the anti-donor response  Loss of donor DC with time Two Pathways of Allo-Recognition  Why is the allo-response so strong? o Unprimed alloreactive T lymphocytes react with unusual vigor against the MHC expressed on APCs o In vitro, alloreactive T cells are activated easily by foreign MHC molecules without previous in vivo priming and are detectable in amazingly high frequencies o The precursor frequency for an alloreactive T cell is 1 – 10% vs. less than 0.0001% for a traditional peptide antigen o Alloreactive T cells meet a high density of alloantigen per cell vs. traditional peptide-specific T cells  Accessory signals are present in the T cell alloresponse Matching Donor and Recipient  ABO blood group typing in all organs (compatibility)  Pre-transplant tissue typing o HLA typing o Matches at HLA A, B and DR are most important for kidney transplantation o Monthly testing for sensitization (Anti-HLA Ab)  At transplant o Cross-matching to detect pre-formed antibodies against donor cells  Why are preformed anti-ABO and anti-HLA important? o Sensitized: presence of antibodies against an antigen o Hyperacute rejection: happens when the recipient has preformed antibodies against ABO or HLA antigens o Graft thrombosis o Graft loss within minutes to hours of reperfusion o Requires allograft nephrectomy (removal of the transplanted kidney) Pretransplantation Testing for Renal Patients  HLA phenotype: patient cells tested with known antisera o Tissue typing – serological (wells contain Ab to known class I and class II) o Genotyping – has replaced HLA serotyping, gives more details about the alleles  HLA antibody screen: known cells tested with patient sera o PRA: Panel Reactive Antibody  A measure of pre-formed Ab in potential recipients  HLA and non-HLA antigens  Against a panel of antigens from multiple donor cells from the “population”  As opposed to a specific donor (a crossmatch)  Estimate of likelihood that they will have antibodies to a donor drawn from that population  Gauges the immune activity of a patient
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