Transplant Immunopathology Flashcards
What is the success of organ / tissue transplants dependent on?
on the ability to deter or prevent an immune reaction
In organ/tissue transplants, the ability of the body to deter or prevent an immune reaction is accomplished by what? (3)
- histocompatibility matching between the donor and recipient
- immunosuppressive therapy of the recipient (e.g., use of antirejection drugs)
- achieving specific unresponsiveness to donor alloantigen(s) (i.e., tolerance).
What is the private, nonprofit organization that manages the organ transplant system in the U.S. under contract with the federal government.
United Network for Organ Sharing (UNOS)
For a successful organ, bone marrow or stem cell transplant (graft), what must be matched for the donor and recipient? (2)
- must be matched for ABO blood groups
- ideally, match as many HLA antigens as possible
Immunosuppression of the recipient (usually using antirejection drugs) is a necessity in all organ, bone marrow, stem cell transplantation, except what? (2)
- in the case of identical twin donor and recipient;
- autologous bone marrow / stem cell transplants
How can transplant rejection and other adverse immune responses be suppressed in organ transplant
- Anti-rejection (immunosuppressant) drugs: (cyclosporine, corticosteroids, tacrolimus, sirolimus, azathioprine, mycophenolate mofetil (MMF))
- Recipient T-cell depletion
- Radiation
The genes that code for _____ are called histocompatibility genes and are localized to a region on the short arm of ______, known as the major _________
- HLA antigens
- chromosome 6
- histocompatibility complex (MHC)
What are the three subgroups of the MHC region in Transplant Histocompatibility Matching
MHC class I, MHC class II, and MHC class III
What does MHC Class I include?
Include the HLA-A, HLA-B, and HLA-C antigens, which are found on almost all human cells
Where are MHC Class II found? What do they include?
- Are chiefly found on immunocompetent cells (macrophages, dendritic cells, Langerhans cells, B-cells, and some T-cells)
- Include the HLA-DP, HLA-DQ, and HLA-DR antigens
MHC Class III has a very different function than class I and II, but it has a _____ between the other two (on chromosome 6), so they are frequently discussed together
locus
Why is it hard for a patient need an organ transplant to find a HLA matched donor?
because there are more than 14,000 HLA alleles accounting for more than 10,000 different HLA proteins.
The current standard for HLA matching between transplant recipient and donor is either an ____ or _____ (preferred) (“high resolution”) HLA allelic match to increase transplant survival
- 8 of 8
- 10 of 10
What is a 10 of 10 HLA allelic match?
HLA-A, -B, -C, -DRB1, and -DQB1 matched.
HLA matching of the transplant donor and recipient is most beneficial for what?
- allogenic bone marrow and stem cell transplants
- (living related donor) kidney transplants
What type of match is considered sufficient in other organ transplants such as heart, lung, liver and pancreatic islet transplantation?
- 6 of 6 HLA match
- in many cases these transplants will be performed without having a zero HLA mismatch donor organ
What factors can affect the benefit derived from HLA matching
donor age, donor type (living vs. dead) and immunosuppression (anti-rejection) protocol
Finding a zero HLA mismatch donor may not be possible for all patients and usually _____ waiting time
- prolongs
(The odds of finding a 6 of 6 HLA match in an unrelated donor is about 1 in 100,000)
What are the 3 categories Bone marrow or hematopoietic stem cell transplants may be
- syngeneic
- allogeneic
- autologous
What is a syngeneic transplant?
from a genetically identical twin, triplet, etc.
(100% HLA matched)
What is an allogeneic transplant?
- from an HLA-matched related or unrelated donor
- Usually at least a 7 out of 8 match at HLA-A, -B, -C and -DRB1 (may be lower)
In allogeneic transplants, what does the term “haploidentical” indicates
an allogeneic transplant from a half (4 out of 8 HLA) matched related donor with only one mismatch per locus
What is an autologous transplant?
a portion of the patient’s own stem cells or bone marrow is removed prior to myeloablative conditioning, screened (to eliminate malignant cells), preserved and reimplanted in the patient after myeloablative conditioning
What are the 3 types of transplant rejections in solid organ transplant?
- Hyperacute Rejection
- Acute Rejection
- Chronic Rejection
What are the subcategories of acute transplant rejection?
- Acute cellular (T-cell mediated) rejection
- Acute antibody-mediated (vascular or humoral) rejection
Hyperacute Rejection is primarily _____ mediated and occurs in the presence of _____ antibody to donor organs
- antibody
- pre-existing
(example: natural IgM antibodies specific for ABO blood group antigens)
When does hyperacute transplant rejection occur?
within minutes of organ transplantation
Hyperacute transplant rejection is a combined process in which both cellular and humoral tissue injuries contribute (i.e., a localized Arthus reaction) marked by what?
by acute inflammation, fibrinoid necrosis of small vessels, and extensive thrombosis
In hyperacute transplant rejection, what happens immediately after the graft is implanted and blood flow is restored
antibodies bind to antigens on the graft endothelium and activate the complement and clotting systems → injury, thrombus formation, and ischemic necrosis of the graft
_______ is the principal cause of early transplant failure
acute transplant rejection
When does acute transplant rejection occur?
- within days of transplantation in the untreated (nonimmunosuppressed) recipient
- may appear suddenly months or even years later, after anti-rejection drugs are tapered or discontinued.
When is Acute cellular (T-cell mediated) rejection most commonly seen?
within the initial months after transplantation
Acute cellular (T-cell mediated) rejection is primarily mediated by what?
both CD4+ and CD8+ T-lymphocytes directed against the donor tissue / organ graft
In Acute cellular (T-cell mediated) rejection, CD4+ T-lymphocytes also secrete ______ and induce ______, which damages the graft
- cytokines
- inflammation
Acute antibody-mediated (vascular or humoral) rejection is primarily mediated by what?
anti-donor antibodies that bind to vascular endothelium and activate complement via the classical pathway
How is Acute antibody-mediated (vascular or humoral) rejection mainly manifested?
by damage to glomeruli and small blood vessels in the transplanted (donor) kidney
Chronic Rejection may occur ____ after an otherwise successful transplantation
months to years
What is chronic transplant rejection primarily caused by?
antibody-mediated vascular damage
Chronic transplant rejection is dominated by ______, often with intimal thickening and vascular occlusion.
Interstitial fibrosis and tubular atrophy with loss of _____ may occur secondary to the vascular lesions
- vascular changes
- renal parenchyma
When does Graft versus host disease (GVHD) occur?
in any situation in which immunologically competent cells or their precursors are transplanted into immunologically incapacitated recipients, and the transferred cells recognize alloantigens in the host
Graft versus host disease (GVHD) occurs most commonly in the setting of what?
allogeneic bone marrow or stem cell transplantation, but rarely also follow transplantation of solid organs rich in lymphoid cells (e.g., the liver).
What is the etiology of Graft versus host disease (GVHD)
When such recipients receive normal bone marrow cells from allogeneic donors, the immunocompetent T-cells present in the donor marrow recognize the recipient’s HLA antigens as foreign and react against them
________ cells from the donor tissue recognize and attack host tissues in Graft versus host disease (GVHD)
CD4+ and CD8+ T
When does acute Graft versus host disease (GVHD) occur?
within 100 days (median: 2 to 3 weeks) after bone marrow or stem cell transplantation
What does clinical manifestation of acute Graft versus host disease (GVHD) result from?
from epithelial cell necrosis in 3 principal target organs: liver, skin, and gut.
Involvement of skin in acute GVHD usually appears where?
first on the neck, ears, and palms of the hands and soles of the feet and then becomes generalized
How does generalized acute GVHD present on the skin?
as a generalized rash and mucosal ulcerations leading to desquamation in severe cases
In acute GVHD, destruction of ______ gives rise to jaundice, and mucosal ____ of the gut results in bloody diarrhea
- small bile ducts
- ulceration
______ is a frequent accompaniment of GVHD.
Immunodeficiency
GVHD affected individuals are profoundly ______ and are very susceptible to infections, mostly with viruses, such as ____ and _____
- immunosuppressed
- CMV
- EBV
In acute GVHD, it is believed that in addition to direct cytotoxicity by CD8+ T-cells, considerable damage is inflicted by what?
cytokines released by the sensitized donor T-cells
Microscopically, graft versus host disease is one of the best examples of a process called _______
single cell apoptosis
Chronic GVHD occurs when?
100 days or more after organ or bone marrow transplantation and may follow the acute syndrome or may occur insidiously
Patients of Chronic Graft versus host disease (GVHD) have extensive _____injury, with destruction of skin appendages and fibrosis of the dermis that may resemble _______
- cutaneous
- systemic sclerosis (scleroderma)
In chronic Graft versus host disease (GVHD) chronic liver disease manifested by _____ is also frequent
cholestatic jaundice
In chronic GVHD, what happens to the immune system?
- The immune system is devastated, with involution of the thymus and depletion of lymphocytes in the lymph nodes.
- The patients experience recurrent and life-threatening infections
_____ symptoms are noted in ~ 80% of patients with extensive chronic GVHD and can cause considerable morbidity.
Oral
Oral manifestations of chronic GVHD resemble what?
those of several autoimmune conditions, including lichen planus, Sjögren’s syndrome, and scleroderma
What does the clinical presentation of oral chronic GVHD include? (7)
- mucosal erythema
- lichen-planus-like changes that can be: reticular; erosive and/or ulcerative
- hyperkeratosis or leukoplakia
- mucosal changes associated with decreased salivary gland function and complaints of dry mouth
- mucoceles
- sclerotic restriction of mouth opening
- taste disturbances
Patients with chronic GVHD are at an increased risk for developing what? How often should they be evaluated for this?
oral cancer and should therefore be evaluated at least twice a year
