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Genetics; Protection II > Solid Organ Transplantation > Flashcards

Solid Organ Transplantation Flashcards

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1
Q

There are two sets of cell surface antigens that serve as the primary marker of transplant survival:

A

 ABO major blood group glycolipids

 Major histocompatibility complex (MHC)

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2
Q

What comprises 100 closely-linked genetic regions occupying 2 centromorgans on the short arm of chromosome 6?

A

MHC

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3
Q

What encode cell surface proteins and human leukocyte atigens (HLA) -> self from none self?

A

MHC genes

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4
Q

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)

A

Class II region

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5
Q

Every nucleated cell displays class I antigens on its cell surface including both B and T lymphocytes

A

Class I products

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6
Q

Have limited distribution namely on monocytes, macrophages and activated T cells

A

Class II products

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7
Q
  • 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”
A

HLA nomenclature

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8
Q

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)?
A

HLA genes

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9
Q

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)?
A

HLA genes

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10
Q

HLA TYPING PROCEDURES

Clinical Outcome

A
  • 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.
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11
Q

CROSSMATCHING STRATEGIES

A

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.

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12
Q

TEST PROCEDURES

A
  1. Complement-dependent Cytotoxicity Assays
  2. Binding Assay Techniques
  3. Serum Screening Procedures
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13
Q

 Standard NIH-CDC
 Amos-modified CDC
 Antihuman globulin-enhanced CDC

A

Complement-dependent Cytotoxicity Assays

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14
Q

 Flow Cytometry

 Enzyme-linked Immunosorbent Assays

A

Binding Assay Techniques

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15
Q

CLINICAL IMPLICATIONS OF CROSSMATCH TESTS

A
  • 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
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16
Q 
Time of Onset: <48 hours
Response: Secondary
Mechanism: Preformed Antibodies
Histopathology: Antibody, Platelet, Granulocyte/Depot
Therapy: None
Success: 0 %
A

Hyperacute Rejection

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17
Q

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%

A

Accelerated Rejection

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18
Q 
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%
A

Acute Rejection

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19
Q

Time of Onset: >60 days
Response: Primary
Mechanism: Humoral Antibody/Non-antigen dependent mechanism
Histopathology: Vascular smooth muscle cell proliferation
Therapy: None
Success: 0 %

A

Chronic Rejection

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20
Q
  • 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)
A

IMMUNOSUPPRESSION

21
Q
  • 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
A

ORGAN PROCUREMENT AND PRESERVATION

22
Q

Types of Organ Donors

A 
 Living Related Donors
 Living Non-related Donors
o Emotionally related donors
o Directed or non-directed
o Commercial donors
 Deceased Organ Donors
23
Q

Living Organ Donors

A

 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

24
Q

What are the two patron

saints of Medicine? Performed the first transplantation by transplanting the leg of a moor into a Caucasian patient

A

Cosmos and Damian

25
Q

first successful kidney transplant
in a dog which was performed at the
Vienna Medical School in Austria

A

1902

26
Q

first animal-to-human kidney

transplant

A

1909

27
Q

first (unsuccessful) human-to human kidney transplant

A

1936

28
Q

Sir Peter Medawar and others begin to identify, understand and explain why transplanted tissues are rejected. Early-stage of research on immunosuppression

A

1940s

29
Q

First temporary kidney transplant
is performed at Peter Bent Brigham Hospital (Now Brigham & Women’s
Hospital) in Boston

A

1945

30
Q

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.

A

1952

31
Q 
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
A

1954

32
Q

first kidney transplant in human

using immunosuppression

A

1958

33
Q

first successful kidney transplant

between fraternal twins

A

1959

34
Q

first successful kidney transplant

between non-twin siblings

A

1960

35
Q

first successful kidney transplant

between non-siblings

A

1961 v

36
Q 
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
A

1972

37
Q

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.

A

1983

38
Q

1st kidney transplantation from a cadaver donor at PGH by Dr. Enrique
Esquivel (Uro)

A

1968

39
Q

1st LRD-KT at UST by Dr. Domingo

Antonio

A

1969

40
Q

1st LRD-KT at UST by Dr. Domingo

Antonio

A

1969

41
Q

homecoming of Filipino transplant
surgeons who trained under Starzle,
Hamburger & Calne

A

1970

42
Q

establishment of the Kidney

Foundation of the Philippines

A

1974

43
Q

15-24 KTs performed

annually

A

1970 – 1980s

44
Q

Pres. Marcos underwent
KT with son Bongbong as donor (NKFP)
= Azathriopine & Steroids

A

August 7, 1983

45
Q

Pres. Marcos’ 2nd Kt

= cyclosporine (Sandimunne)

A

September 7, 1984

46
Q

1st kidney/liver

transplant was done at NKTI

A

September 18, 1990

47
Q

1st heart transplant done at Makati Medical Center

A

May 28, 1994

48
Q

1st segmental liver

transplant from LRD done at NKTI

A

April 12, 1996

49
Q

first kidney transplant was done at CDUH between a 28-year old ESRD patient and his 22-year old brother as donor

A

August 2007

Genetics; Protection II (11 decks)

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