First Aid, Chapter 8, Immunologic Disorders, Immune Rejection and Organ Transplantation Flashcards

1
Q

Why does rejection occur in solid organ transplantation?

A
  • Rejection revolves around the donor’s immune reaction to the vasculature of the transplanted organ.
  • GVHD can occur due to harbored, competent immune cells in the donor graft attaching the immunosuppressed host.
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2
Q

Why does rejection occur in bone marrow transplant?

A

Require human leukocyte antigen (HLA) compatibility, or matching

Major complication tends to be graft-versus-host disease (GVHD)

Rejection occurs when the host immune system remains competent. It will recognize the donor cells as foreign and kill them mainly through Tlymphocyte- and natural killer (NK) cell-mediated reactions

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3
Q

What chromosome is the MHC complex on? How many classes?

A
chromosome 6
class 1, 2, and 3
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4
Q

What HLA genes does the class 1 region of the MHC complex carry?

A

The class I region has both classical (A, B, C) and nonclassical HLA genes. The nonclassical genes (E, G, F) have unique properties. HLAG and F are expressed on the extra villous trophoblast. Their key role is to protect the fetus from maternal immune rejection. They have a more limited polymorphic profile.

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5
Q

How are HLA genes named?

A

The HLA is designated by a letter and a single- or a two-digit number.

Class I antigens = A, B, or C + digit
o Example: HLA*A0201

Class II antigens = D + M, O, P, Q, or R + A or B (for α or β chain) + digit
o Example: HLA-DRB1*0401

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6
Q

How are HLAs inherited?

A

HLA is expressed in a codominant fashion. Each locus has two alleles; and, as individuals, we each receive one from our mother and one from our father.

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7
Q

What is direct vs. indirect allorecognition?

A

Direct:
donor APC with donor MHC is recognized by recipient T cell

Indirect: 
Recipient APC with Recipient MHC class 2 presents exogenous donor ag (endocytosed by APC) to recipient T cell
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8
Q

What are syngeneic, allogeneic, and xenogeneic transplants?

A

Syngeneic: Genetically identical, twins

Allogeneic: Nongenetically identical. The reactive antigens are different within the same species (e.g., HLA or other polymorphic gene products): These antigens are alloantigens.

Xenogeneic: Graft across species

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9
Q

Which organs do not require immunosuppression?

A

Cornea, bone, and joint tissues do not require immunosuppression.

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10
Q

What is the mediator in hyperacute rejection? timing? pathophysiology? What type of transplant is it a big issue in? What should you do if it happens?

A

Preexisting Ab

On the table after anastomosis Minutes to hours

Ab to antigen compliment activation and endothelial damage thrombosis, PMN

Black organ, ABO incompatible (natural IgM). Big issue in xenotransplantatio n: Remove!

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11
Q

What is the mediator in accelerated rejection? timing? pathophysiology? What should you do if it happens?

A

Preexisting Ab but minor antigens not in typical screening

Within 2–5 days

IgG noncompliment–fixing Ab, endothelial damage, thrombosis, and vasculitis

Try immunosuppression

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12
Q

What is the mediator in acute rejection? timing? pathophysiology? What type of cell is involved? What should you do if it happens?

A

Alloreactive Tlymphocyte +/– Ab

After 7 days to 3 months

Direct killing by T lymphocyte, cell infiltrations, and endovasculitis

CD8+ cell and steroids

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13
Q

What is the mediator in chronic rejection? timing? pathophysiology? What type of cell is involved and what does it cause?

A

DTH-like reaction T cells, cytokines

Months to years

Vessel smooth muscle proliferation, fibrosis, and occlusion

Alloreactive CD4+ graft vasculopathy, or accelerated graft arteriosclerosis

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14
Q

What is a mixed leukocyte reaction (MLR)?

A

Donor A’s mononuclear cells are cultured with donor B’s mononuclear cells. Donor A’s cells are irradiated or drug-treated to make them incapable of proliferation. Since they are foreign to donor B, the donor B cells will clonally expand in both CD4+ and CD8+ effector cells.
The proliferation can be measured by incorporation of radioactive material in the media. If there was no proliferation, the donor A cells would be seen as self and, thus, ignored.

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15
Q

What is a full match for bone marrow transplantation?

A

A full match is considered six out of six, at A, B, and DRB1 alleles. A match does not have to go out to the four digits and an allele group; the first two numbers will suffice. Trends are changing, and sequence-based four-digit allele typing is being used in some types of BMT transplants. Ten-allele matches are also becoming more common, adding C and DQ to the search.

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16
Q

Which tissues can be transplanted across ABO?

A

Cornea, bone, joint tissues, and hematopoietic stem cells

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17
Q

What cells do stem cell transplants use?

A

CD34+

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18
Q

What diseases are stem cell transplants used for?

A

SCT is by far most widely used to treat malignancy; Also, immunodeficiency, SCT is the only definitive cure for many immunodeficiencies. Also, aplastic anemia and certain genetic disorders.

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19
Q

What are sources of stem cell transplanation?

A

Bone marrow

Peripheral blood

Cord blood

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20
Q

What is the advantage of using cord blood for SCT? Disadvantage?

A

Immunologically immature and enriched naturally with CD34+ cells; ease of collection and less stringent HLA matching

Disadvantage: Small dose of CD34+ cells, and slower engraftment, Multiple cords needed.

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21
Q

What is the order of risk for allogeneic transplant rejection from highest to lowest? And by MCH class?

A
Mismatched Unrelated 
Mismatched Cord 
Matched Unrelated 
Matched Cord 
Matched First-Degree Relative 
Syngeneic 

Class II Mismatch > Class I Mismatch

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22
Q

What is needed to harvest peripheral blood for stem cells?

A

Mobilization for enrichment of stem cells and 15 mL/kg of donor for harvest

23
Q

What are some risks for nonengraftment of SCT?

A

Other risks for nonengraftment include: LORD NIC
Low stem cell dose
Older age of donor Recipient Tlymphocyte function
Degree of HLA mismatch
Natural killer cell function
Infection
Conditioning regimen

24
Q

To which HLA loci does a 6/6 HLA match refer?

A

The donor and recipient have been matched at HLA-A, HLA-B, and HLA-DRB1

25
Q

What are indicationsof SCT?

A

Malignancies such as leukemia are the most common reasons for SCT. Solid tumors such as neuroblastoma are treated medically, and the patient is rescued with a previously harvested autologous SCT.

Hematopoietic disorders such as aplastic anemia, myelodysplasia, and hemoglobinopathies have been treated with SCT.

Inborn errors of metabolism, such as Hurler’s syndrome and osteopetrosis, have been treated using SCT.

In cases of primary immunodeficiency, SCT has been used to cure the immunologic defects in the following diseases:

Severe combined immunodeficiency (SCID)

Chronic granulomatous disease

X-linked hyper IgM syndrome

Wiskott-Aldrich syndrome

Chediak-Higashi syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX)

Familial hemophagocytic lymphohistiocytosis

Griscelli’s syndrome

26
Q

How does graft versus leukemia work? What cell receptor is involved?

A

In the graft-versusleukemia effect the graft T lymphocytes contribute to the eradication of the tumor. These same T lymphocytes can cause GVHD.

The inhibitory killer immunoglobulin-like receptors, also called killer inhibitory receptors (KIRs), on donor NK cells are inhibited by cells that display HLA I markers that they recognize. Recipient leukemia cells express HLA I that is different from donor HLA I and results in donor NKmediated cellular killing of leukemic cells.

27
Q

What type of SCID phenotype does the best with SCT?

A

. Patients with T–, B+, and NK– SCID tend to do best. These patients, without matched siblings, have traditionally undergone haploidentical transplant with graft T-lymphocyte depletion and no conditioning.

28
Q

What type of SCID phenotype does the worst with SCT? What is the most common adverse effect of SCT in SCID?

A

Patients with ADA (T–, B–, and NK–) tend to have the worst prognosis. The presence of NK cells with activity might make conditioning necessary. X-linked SCID (with B-lymphocytes present, but not functional) transplants have been attempted without conditioning; however, the B-lymphocyte engraftment is low and may require lifelong Ig replacement. Conditioning improves B-lymphocyte engraftment, but the agents used for host conditioning have other adverse effects to consider. Graft-versus-host disease (GVHD) is the most common adverse effect.

29
Q

What makes the use of haploidentical individuals in SCID unique?

A

SCID is unique in the use of haploidentical transplants due to the almost total lack of host immunity. Most other types of immune deficiency disease that require SCT necessitate some kind of conditioning protocol that is disease specific. SCID conditioning may be nonmyeloablative.

30
Q

What types of conditioning for SCT for primary immunodeficiency are there? Why is it needed?

A

Vary from myeloablative, to nonmyeloablative, to reduced intensity, to no conditioning.

If T-lymphocyte function is intact, an ablative conditioning regimen is usually required.

31
Q

What is myoablative conditioning? What are some methods/medications?

A

Destroys the host hematopoietic cells. Bone marrow needs to be replaced. Includes total body irradiation, busulfan, etoposide, cytarabine, cyclophosphamide, cytosine arabinoside, anti-CD45, anti-CD66, antiCD20 antibodies.

32
Q

What is nonmyeloablative conditioning? What are some methods/medications?

A

Causes minimal cytopenia with significant lymphopenia. Includes fludarabine, cyclophosphamide, antimyocyte globulin (ATG), low-dose total body irradiation, anti-CD52 Ab. Good if graft-versustumor effect is desired, minimizes GVHD, minimizes graft rejection, minimizes opportunistic infections. Donor T cells will eliminate host hematopoietic cells with time.

33
Q

What is reduced intensity conditioning? What are some regimens/medications? Which patients is it used for?

A

Causes minimal cytopenia with significant lymphopenia. Includes fludarabine, cyclophosphamide, antimyocyte globulin (ATG), low-dose total body irradiation, anti-CD52 Ab. Good if graft-versus tumor effect is desired, minimizes GVHD, minimizes graft rejection, minimizes opportunistic infections. Donor T cells will eliminate host hematopoietic cells with time.

34
Q

What are potential toxicities for conditioning?

A

Toxicities include mucositis, nausea, emesis, alopecia, diarrhea, rash, peripheral neuropathy, infertility, interstitial lung disease, sinusoidal obstruction syndrome. Total body irradiation complications include abnormal pulmonary function, cataracts, sicca syndrome, and thyroid dysfunction.

35
Q

What is the difference between serologic level and sequence level?

A

Alleles are designated first by two-digit numbers, indicating a group of alleles that encode a particular antigen at the serologic level. The allele is further subtyped by a two-digit number, signifying the specific allele at the sequence level.
The difference between the serologic level and the sequence level is that an antigen that the antibody recognizes may be encoded by different polymorphisms. The antibody might not be able to tell the difference between these polymorphic sequences; however, T-lymphocyte epitopes that are linear and presented in the context of the HLA molecules might induce rejection to a polymorphism that was serologically indistinguishable. Thus sequencing gives the so called high resolution typing.

36
Q

What is graft vs. host disease?

A

Graft-versus-host (GVH) reaction is the recognition of the host tissues by mature donor T lymphocytes as being foreign through the recognition of host alloantigens

37
Q

What predisposes to GVH?

A

Traditional HLA matching is based on A, B, and DR alleles. Mismatch at any allele increases the risk of GVH reaction. Even in a six-out-of-six matched transplant, GVH can happen due to the other mismatched HLA alleles or to minor HLA antigens and non-HLA-encoded antigens.

Other important non-HLA factors are polymorphisms in innate immunity components, such as nucleotide oligomerization domain (NOD) and Toll-like receptors (TLRs).

38
Q

What are the important cytokines in GVH?

A

IL-10, TNFα, and IFNγ.

39
Q

What cells are involved in acute vs. chronic GVH?

A

Acute: CD45RO+ T-lymphocyte and neutrophil engraftment (important)

Chronic: CD4+ helper T lymphocytes

40
Q

What is the timing of acute vs. Chronic GVH?

A

Acute 100 days

41
Q

What is the prophylaxis of acute GVH vs. chronic GVH?

A

Acute: Methotrexate, cyclosporine, tacrolimus, corticosteroids, antithymocyte globulin, and
Tlymphocyte depletion

Chronic:
T-lymphocyte depletion

42
Q

What is the treatment of acute GVH vs. chronic GVH?

A

Acute: Corticosteroids; alternatives include cyclosporine, tacrolimus, antithymocyte globulin, and mycophenolate

Chronic:
Corticosteroids, corticosteroids plus cyclosporine, thalidomide, and ursodeoxycholic acid

43
Q

What are clinical manifestations of acute GVH? Chronic GVH?

A

Acute: Maculopapular rash, Watery diarrhea, severe abdominal pain, bloody diarrhea, and ileus, Cholestatic hyperbilirubinemia, fever

Chronic:
Skin: Dyspigmentation, alopecia, sclerotic features, and nail dystrophy loss
Mouth: Ulcers, xerostomia
Eyes: Dry and sicca syndrome
Musculoskeletal: Fasciitis, myositis, and contractures
Gastrointestinal:
Weight loss, webs, and strictures
Liver: Jaundice transaminitis
Lung : Restrictive or obstructive defects and bronchiolitis obliterans
Heart: Pericarditis
Marrow: Cytopenias

44
Q

What is sinusoidal obstruction syndrome (hepatic sinusoidal veno-occlusive disease [VOD]) an adverse effect of?

A

Conditioning therapy and drug toxicity, Single-dose radiation, alkaloids (e.g., busulfan, cyclosporine, and methotrexate) for prophylaxis, and sirolimus.

45
Q

What is the major factor in whether a SCT will allow for long term survival?

A

chronic GVH

46
Q

What are the seattle criteria and baltimore criteria for sinusoidal obstruction syndrome?

A

Seattle Criteria. Two of the three symptoms within 20 days of SCT: bilirubin > 2 mg/dL, hepatomegaly or right upper quadrant pain, >2% weight gain due to fluid retention

Baltimore Criteria. Bilirubin >2 mg/dL plus two of the three symptoms: tender hepatomegaly, >5% weight gain, ascites

47
Q

How can acute and chronic GVH be prevented? What is the downside of doing this?

A

T-lymphocyte depletion is the major way of preventing or reducing the risk of both acute and chronic GVH reactions. Mature T lymphocytes from the graft are implicated in the disease. Eliminating them might represent an advantage from this perspective; however, if all mature T lymphocytes are purged, engraftment would be severely affected, as would immune reconstitution, graft-versus-tumor effect, and infection complications.

48
Q

What does complete depletion of T lymphocytes in SCT lead to?

A

nonengraftment

49
Q

What are some methods to cause T lymphocyte depletion?

A

These methods involve ex vivo manipulation of the donor cells with methods such as soybean lectin and E-rosetting, as well as E-rosetting and CD34+ selection, and monoclonal antibodies like anti-CD3, anti-CD2, anti-CD6, anti-CD25, or antiCD52.

50
Q

What are the clinical features of SOS (sinusoidal obstruction syndrome)?

A

Tender hepatomegaly, weight gain due to fluid retention, and hyperbilirubinemia

51
Q

What might happen after maternal engraftment in SCID?

A

SCID: During birth a maternal-fetal transfusion of blood and immune cells can occur. When mature, maternal T lymphocytes engraft the baby, a maternal GVH reaction may occur with the infant’s tissue as a target. In this case, the cells are likely CD8+ and clonal.

52
Q

How can blood transfusions cause GVH?

A

Blood transfusions: In an immunocompromised host, blood transfusion with a nonirradiated or nonleukoreduced product can result in competent donor T lymphocytes, which are transfusion-derived, causing GVH reaction. Very uncommonly, this can even happen in an immunocompetent host when whole blood is given.

53
Q

How do you know when neutrophil and platelet engraftment have occurred?

A

Neutrophil engraftment is defined as 3 consecutive days with an ANC ≥ 0.5 × 10^9/L, or one day with a count of ≥1.0 × 10^9/L.

Platelet engraftment is defined as the first day when the platelet count is >20 × 10^9/L on 3 consecutive measurements within 7 days, with no transfusions in the preceding 7 days.

54
Q

Which type of stem cell transplant takes longest to engraft?

A

Umbilical cord cells take the longest of the stem cells to engraft.