Solid Organ Transplantation Flashcards
There are two sets of cell surface antigens that serve as the primary marker of transplant survival:
ABO major blood group glycolipids
Major histocompatibility complex (MHC)
What comprises 100 closely-linked genetic regions occupying 2 centromorgans on the short arm of chromosome 6?
MHC
What encode cell surface proteins and human leukocyte atigens (HLA) -> self from none self?
MHC genes
Also contains four genes that encode proteins that transport peptides into the ER for loading into the class I molecule (TAP 1 and TAP 2)
Class II region
Every nucleated cell displays class I antigens on its cell surface including both B and T lymphocytes
Class I products
Have limited distribution namely on monocytes, macrophages and activated T cells
Class II products
- Nomenclature system is based either:
Epitopes defined immunologically using either serological or cellular techniques
Biochemically by nucleotide sequence of allelic genes - The former uses HLA followed by a hyphen represents the MHC; the capital letters thereafter – A, B, C, DR, DP or DQ
Designate the segregant series - The number stipulates the specific allele, beginning with the number 1.
- The second nomenclature system is based on nucleotide sequence.
- In the 2nd nomenclature, HLA followed by hyphen represents the MHC; a series of capital letters, with or without a number, designates a specific locus or “segregant series”
HLA nomenclature
What display classic Mendelian inheritance -> each individual inherits a single chromosome (haplotype) from each parent and therefore, has 2 HLA haplotypes (one paternal and one maternal in origin)
- Haplotypes are usually inherited intact although in 2% recombination between HLA-A and HLA-DR occur during meiosis resulting in new haplotype.
- Since the expression of HLA A, B, and DR antigens is codominant, each person displays a phenotype that includes two specificities for each locus (2 each for HLA A, B and DR)?
HLA genes
What display classic Mendelian inheritance -> each individual inherits a single chromosome (haplotype) from each parent and therefore, has 2 HLA haplotypes (one paternal and one maternal in origin)
- Haplotypes are usually inherited intact although in 2% recombination between HLA-A and HLA-DR occur during meiosis resulting in new haplotype.
- Since the expression of HLA A, B, and DR antigens is codominant, each person displays a phenotype that includes two specificities for each locus (2 each for HLA A, B and DR)?
HLA genes
HLA TYPING PROCEDURES
Clinical Outcome
- Among living-related donor-recipient combinations, grafts from HLA-identical siblings display the best survival followed by one haplotype matches
- Conflicting reports on correlation between HLA matching and graft survival
- 1.06 relative risk of graft loss for each HLA mismatch. Increasing number of HLA mismatches are associated with higher adjusted relative risks of failure of first renal transplant
- Numerous individual and cooperative transplant center reports have failed to observe a benefit of HLA-A, B and DR donor-recipient matching.
- Disparity is attributed to differences in immunosuppressive protocols, patients demographics, cross-match criteria, etc.
- Kidneys from living, genetically unrelated donors bearing full HLA mismatches display outcomes superior to those of organs from cadaveric donors with the same degree of mismatch.
CROSSMATCHING STRATEGIES
Histocompatibility testing seeksto identify donor-recipient combinations likely to yield successful transplants utilizing three principles:
ABO Blood Group Compatibility
HLA Matching
Donor-Specific Cross-matching
- Besides ABO compatibility, the pre-transplant crossmatch is generally regarded as representing the most important procedure performed in the histocompatibility laboratory.
TEST PROCEDURES
- Complement-dependent Cytotoxicity Assays
- Binding Assay Techniques
- Serum Screening Procedures
Standard NIH-CDC
Amos-modified CDC
Antihuman globulin-enhanced CDC
Complement-dependent Cytotoxicity Assays
Flow Cytometry
Enzyme-linked Immunosorbent Assays
Binding Assay Techniques
CLINICAL IMPLICATIONS OF CROSSMATCH TESTS
- When it was documented that a positive crossmatch predicted early graft rejection, the standard microlymphocytotoxicity crossmatch was introduced was introduced into routine renal transplant practice.
- High risk for positive crossmatch
Multiparous females
Retransplants
Recipients of Blood Transfusion - The presence of antibodies that lysed T cells (a positive T cell cross reaction) contraindicates transplantation whereas B cell positive reactions were not associated with graft failure in some reports.
- The antihuman globulin (AHG) crossmatch enhance the sensitivity of the tests beyond that was achieved by standard CDC technique.
An AHG positive result is an absolute exclusion of a recipient from transplants from that donor. - Significance of a positive historical crossmatch when the result with the current or pretransplant serum is negative.
Whereas a positive crossmatch result using a historical positive serum represents a contraindication for retransplantation. It does not seem to have the same adverse prognostic significance for a candidate for primary renal transplant. - Outcome of renal transplantation depends upon multiple factors:
Immunosuppressive regimen
HLA Antigen matching
Ethnicity
Gender
Degree of presensitization
Transfusion history
Time of Onset: <48 hours Response: Secondary Mechanism: Preformed Antibodies Histopathology: Antibody, Platelet, Granulocyte/Depot Therapy: None Success: 0 %
Hyperacute Rejection
Time of Onset: 3-5 days
Response: Secondary
Mechanism: Preformed non-C’ binding Ab, cellular immunity
Histopathology: Hemorrhage
Therapy: Polyclonal anti-lymphocyte glublin/plasmapharesis/cyclosphamide
Success: 60%
Accelerated Rejection
Time of Onset: >6 days Response: Primary Mechanism: Cellular Immunity Humoral Immunity H: Lymphocyte Endovasculitis Infiltrate T: Steroids/OKT3 Steroids/OKT3 Success: 80-90% 60-85%
Acute Rejection
Time of Onset: >60 days
Response: Primary
Mechanism: Humoral Antibody/Non-antigen dependent mechanism
Histopathology: Vascular smooth muscle cell proliferation
Therapy: None
Success: 0 %
Chronic Rejection
- The most aggressive immunosuppression is total body irradiation. This method completely eliminates the bone marrow that is responsible for the production of lymphocytes.
- In the early sixties, xortisone-based drugs (Steroids) and cell synthesis inhibitors (Azathioprine), contributed to the success obtained in renal transplantation. The team of STARZL made fundamental discovery: rejection was a reversible process.
- Other drugs were developed. All had the aim to stop the attack of the lymphocytes.
- The solution came with the next discovery: Hybridoma technology. Cells with an infinite multiplication capacity (such as leukemia cells) were coupled to the animal cells, in this way guaranteeing a more constant and more selective antibody production.
- Cyclosporine-based immunosuppression was introduced in the early eighties.
The drug is a kind of antibiotic that is produced by spores found in Norwegian fields. - Other drugs were then developed and nowadays a multitude of efficient drugs are available for clinical usage. A frequently used drug, Tacrolimus (FK506), is produced by the spores discovered at Mount Fuji in Japan. Tacrolimus, like Cyclosporine, is a cornerstone immunosuppressant. One of its benefits is the possibility to reduce the amount of steroids used in combination, or to stop them altogether. This is important, as steroids are often responsible for physical and psychological problems in transplant patients. Other newer adjunctive therapies available for clinical usage are mycophenolate mofetil, rapamycin and chimerized or humanized antibodies (Basiliximab or Daclizumab)
IMMUNOSUPPRESSION
- The biggest problem faced by transplant centers worldwide is the extreme shortage of organ donors
- Different countries have varying advocacy campaigns to increase its organ procurement
ORGAN PROCUREMENT AND PRESERVATION
Types of Organ Donors
Living Related Donors Living Non-related Donors o Emotionally related donors o Directed or non-directed o Commercial donors Deceased Organ Donors
Living Organ Donors
Surgeons commonly operate on a healthy individual
Living donor transplantation possess a unique set of medical, ethical, financial and psychosocial problems
Living donors offer several advantages for the recipient
What are the two patron
saints of Medicine? Performed the first transplantation by transplanting the leg of a moor into a Caucasian patient
Cosmos and Damian
first successful kidney transplant
in a dog which was performed at the
Vienna Medical School in Austria
1902
first animal-to-human kidney
transplant
1909
first (unsuccessful) human-to human kidney transplant
1936
Sir Peter Medawar and others begin to identify, understand and explain why transplanted tissues are rejected. Early-stage of research on immunosuppression
1940s
First temporary kidney transplant
is performed at Peter Bent Brigham Hospital (Now Brigham & Women’s
Hospital) in Boston
1945
first successful kidney
transplanted from a female traffic
accident fatality and implanted into her son. The kidney initially functioned well
but was rejected 22 days later.
1952
The first successful live donor human kidney transplant beetweel identical twin brothers, took place at the Peter Bent Brigham Hospital in Boston, Massachusetts. The transplanted kidney functioned for 8 years. - Ronald Herrick donated a kidney to his identical twin, Richard, in a pioneering operation on December 23, 1954 performed by the team of Dr. Joseph Murray. - Ronald was 23 when he donated and died at the age of 79
1954
first kidney transplant in human
using immunosuppression
1958
first successful kidney transplant
between fraternal twins
1959
first successful kidney transplant
between non-twin siblings
1960
first successful kidney transplant
between non-siblings
1961 v
Jean Borel discovered the immunosuppressant properties of cyclosporine, a drug widely used in organ transplantation between unrelated people to reduce the activity of the patient’s immune system and so the risk of rejection
1972
Cyclosporine was approved by the
FDA for use as an immunosuppressant drug. It was recognized as the most
successful anti-rejection medication
developed to date.
1983
1st kidney transplantation from a cadaver donor at PGH by Dr. Enrique
Esquivel (Uro)
1968
1st LRD-KT at UST by Dr. Domingo
Antonio
1969
1st LRD-KT at UST by Dr. Domingo
Antonio
1969
homecoming of Filipino transplant
surgeons who trained under Starzle,
Hamburger & Calne
1970
establishment of the Kidney
Foundation of the Philippines
1974
15-24 KTs performed
annually
1970 – 1980s
Pres. Marcos underwent
KT with son Bongbong as donor (NKFP)
= Azathriopine & Steroids
August 7, 1983
Pres. Marcos’ 2nd Kt
= cyclosporine (Sandimunne)
September 7, 1984
1st kidney/liver
transplant was done at NKTI
September 18, 1990
1st heart transplant done at Makati Medical Center
May 28, 1994
1st segmental liver
transplant from LRD done at NKTI
April 12, 1996
first kidney transplant was done at CDUH between a 28-year old ESRD patient and his 22-year old brother as donor
August 2007
