Transplant Immunology Flashcards
graft
cells, tissues, or organs that are transplanted
____ is the major barrier to transplantation medicine
Organ availability is the major barrier to transplantation medicine
Most common transplants (top 3)
- Kidney
- Liver
- Heart
___ are a common transplant that do not have the immunological barriers that are common to almost all other allografts. They are removed from all deceased donors.
Corneal transplants are a common transplant that do not have the immunological barriers that are common to almost all other allografts. They are removed from all deceased donors.
Living vs deceased donors
- Living donors have better outcomes than deceased donors on average
- Living donors may provide kidney; lobe of a lung; partial liver, pancreas or intestine
- Deceased donors may provide any organ
- Brain dead donors best outcomes on average among all deceased donors
- Circulatory death donors second best outcomes among all deceased donors
Organs derived from deceased donors are sometimes referred to as ___.
Organs derived from deceased donors are sometimes referred to as cadaveric.
Circulatory death donors
Died recently, usually from trauma, opiate overdose, or terminally ill donors after voluntary cessation of life support
Factors in matching: Kidney
Factors in matching: Liver
Factors in matching: Lung
Factors in matching: Heart
Some transplant criteria applied to several different organs
- Height and weight of donor/recipient (to ensure physiologic/metabolic compatibility)
- Immunocompatibility
- Blood group
- Presence of antibodies for donor cells
Since patients with no renal function can be kept alive by dialysis until a kidney becomes available, one criteria for waiting list placement of these patients is . . .
Since patients with no renal function can be kept alive by dialysis until a kidney becomes available, one criteria for waiting list placement of these patients is the time they have been dialysis‐dependent
Types of living donation: Related
Blood relatives of transplant candidates including brothers, sisters, parents, children (over 18 years of age), aunts, uncles, cousins, half brothers & sisters, nieces and nephews
Types of living donation: Non-related
Individuals emotionally close to, but not related by blood to transplant candidates, including spouses, in-law relatives, close friends, coworkers, neighbors or other acquaintances.
Types of living donation: Non-directed
Individuals who are not related to or known by the recipient, but make their donation purely out of selfless motives. This type of donation is also referred to as anonymous, altruistic stranger, and stranger-to-stranger living donation
Types of living donation: Paired
Consists of two kidney donor/recipient pairs whose blood types are not compatible. The two recipients trade donors so that each recipient can receive a kidney with a compatible blood type
Even without the advantage of shared MHC alleles, organs removed from living donors . . .
Even without the advantage of shared MHC alleles, organs removed from living donors are in better condition, that is suffered less ischemic damage, then those removed from cadavers, and therefore also do better in the recipients
Ethical and Social Considerations of Transplantation
- Risk to donor
- Compensation for donors
- “Transplantation tourism”
- Waiting lists and triage
- Racial/ethnic minority donor shortages
- Consent for deceased organ donation
- Definitions of death for deceased donors
- Expense/resources
Transplantation tourism
The phenomenon of patients in need of organs traveling to countries where there are more organs available
Rejection
An inflammatory reaction which a recipient mounts against a graft, which can cause graft injury and failure. Mediated by adaptive immunity.
autologous graft
A graft transplanted from one individual to the same individual
syngeneic graft
A graft transplanted between two genetically identical individuals
allogeneic graft (or allograft)
A graft transplanted between two genetically different individuals of the same species
xenogeneic graft (or xenograft)
A graft transplanted between individuals of different species
alloantigens
The molecules that are recognized as foreign on allografts
xenoantigens
The molecules that are recognized as foreign on xenografts
___ are the antigens of allografts that are as the principal targets of rejection
MHC molecules (HLA) are the antigens of allografts that are as the principal targets of rejection
Historically, MHC genes were 1st defined as . . .
Historically, MHC genes were 1st defined as genes causing graft rejection, hence the term histocompatibility
the chance that 2 siblings will have the same MHC alleles is . . .
the chance that 2 siblings will have the same MHC alleles is 1 in 4
___ makes finding histocompatible donors much more probable than it would be if ___.
The existence of HLA haplotypes makes finding histocompatible donors much more probable than it would be if HLA genes were inherited entirely independently.
Direct vs indirect allorecognition
- Direct: Self T cell sees foreign MHC on allograft surface and is activated. Tends to lead to CD8-mediated rejection via granzyme killing.
- Indirect: Self T cell is presented processed foreign MHC which has been taken up by an APC and presented on self MHC molecules as peptide antigen. Tends to lead to CD4-mediated inflammatory response and anti-graft antibody generation.
Direct allorecognition diagram
Indirect allorecognition diagram
___ is one of the strongest immune responses known.
The response to MHC antigens on another individual’s cells is one of the strongest immune responses known.
Many of the alloreactive cells following transplant are . . .
Many of the alloreactive cells following transplant are already expanded clones of memory T cells from previous infections
minor histocompatibility antigens
Non-MHC polymorphic antigens that induce graft rejection
Minor histocompatibility antigens are targets of rejection responses in ___ and in ___.
Minor histocompatibility antigens are targets of rejection responses in blood transfusions and in graft vs host reactions following hematopoietic stem cell transplant.
Sources of attack on an allograft
- Newly-activated T cells which are presented antigen from the graft
- Already long-standing circulating memory cells which are re-activated by graft antigen
Graft rejection is sub-classified into . . .
- Hyperacute (minutes post-transplant)
- Acute (weeks to months post-transplant)
- Chronic (years post-transplant)
- All of the above broken into “cell-mediated” or “antibody-mediated”
Hyperacute rejection
- Occurs within minutes of transplantation
- Characterized by thrombosis of graft vessels and ischemic necrosis of the graft
- Mediated by circulating antibodies specific for antigens on graft endothelial cells present before transplantation
- Maybe be natural IgM antibodies specific for ABO blood group antigens
- Antibodies bind to graft vascular endothelial antigens, activate complement and clotting systems, leading to endothelial injury and thrombus formation
- Uncommon nowadays as it can be avoided by careful pre-transplant testing
How can surgeons detect hyperacute rejection mid-operation?
They describe rapid blanching of the graft as blood supply stops
Histology of hyperacute rejection of glomerulus
___ were first recognized as the barriers to transfusion of blood cells between humans
ABO blood group antigens were first recognized as the barriers to transfusion of blood cells between humans
ABO blood group antigens
- carbohydrate structures on membrane glycoproteins or glycosphingolipids, expressed on red blood cells, endothelial cells, and many other cell types
- core glycan that may be modified by addition of either of two different terminal sugar residues
- Three alleles of the gene encoding the enzyme, one adds a N-acetylgalactosamine, one adds galactose, and one that is inactive and cannot add either. Each person inherits two of the three alleles
*
Natural antibodies against ABO
- they are made in people without overt of exposure to the antigen from another person’s blood cells or other tissues
- The stimulus for production of these natural antibodies is likely the presence of identical carbohydrate structures made by commensal gut bacteria
- natural antibodies are IgM’s
ABO antigen table
Principle cause of early graft failure nowadays
- Acute rejection
- Occurs within days or weeks after transplantation
- Mediated by CD4+ and CD8+ T cells and antibodies specific for alloantigens
- T cells may react against cells in graft parenchyma and vessels
- Antibodies contribute especially to the vascular component of acute rejection by complement
- Current immunosuppressive mainly prevent and reduced acute rejection by blocking the activation of alloreactive T cells
Acute rejection diagram
Chronic Rejection
- Indolent form of graft damage that occurs over months or years, leading to progressive loss of graft function
- Manifests as fibrosis
- T cells that react against graft alloantigens, secrete cytokines, stimulate the proliferation and activities of fibroblasts and VSMC
- Gradual atherosclerosis of graft blood vessels
- Alloantibodies also contribute
- Chronic rejection is refractory to most therapies that work on acute rejection
Refractory
Stubborn or unmanageable
___ is the reason why heart transplants or kidney transplants survive in the host for an average of only 10 years
Chronic rejection is the reason why heart transplants or kidney transplants survive in the host for an average of only 10 years
Chronic rejection diagram
General principles for preventing allograft rejection
- Choose donors to minimize immune incompatibilities with recipient
- Immunosuppressive drugs for induction and then maintenance of immunosuppression
- Induce donor specific tolerance in the recipient
Strategies to Avoid Hyperacute and Acute Rejection
- Blood typing for ABO compatibility
- Cross matching (Test for preformed antibodies in recipient that recognize antigens on the identified donor’s blood leukocytes)
- Panel reactive antibodies (Test for preformed antibodies against panels of common MHC molecules, which would indicate prior exposure to and sensitization by allo MHC molecules)
Cross match and Panel reactive Ab diagram
Tissue typing
Identifying HLAs expressed by tissue
Particularly critical to hematopoietic stem cell transplantation
HLA typing is done mostly by ___
HLA typing is done mostly by PCR‐based methods with donor and recipient leukocytes as sourced of DNA
Immunosuppressants used in transplanation
- Calcineurin inhibitors (tacrloimus and cyclosporine)
- Rapamycin
- Mycophenolate mofetil
- Corticosteroids
- Anti-thymocyte globulin (used to treat rejection, not for maintenance)
- Anti–IL-2 receptor (CD25) antibody (used to treat rejection, not for maintenance)
- CTLA4-Ig (belatacept)
- Anti-CD52 (alemtuzumab) (used occasionally for induction, but not maintenance)
Transplant Immunosuppression diagram (mechanisms of drugs involved)
Graft tolerance
- The induction of long term unresponsiveness to graft alloantigens, without the need for immunosuppression
- Trials are ongoing, as with all tolerogenic vaccines currently
- No practical methods are available yet, but likely will be in the not-so-distant future
Stem cell transplant and later histocompatibility
Stem cell transplant permanently tolerizes an animal to organs from the donor
____ results in painless swolen lymph nodes.
____ results in painful swolen lymph nodes.
Lymphoma results in painless swolen lymph nodes.
Metastatic cancer results in painful swolen lymph nodes.
Any skin cancer should be biopsied using the ___ method.
Any skin cancer should be biopsied using the deep shave method.
If someone really has to be on prednisone chronically, the goal dose is . . .
5 mg / day or below
To screen for cell-mediated rejection, stain with ____.
To screen for antibody-mediated rejection, stain with ____.
To screen for cell-mediated rejection, stain with H and E.
To screen for antibody-mediated rejection, stain with anti-C4d fluorophore.
The best treatment for post-transplant lymphoproliferative disorder
Acyclovir and decrease in dose of immunosuppressive drug
Why does mycophenylate mofetil work so well against T cells?
Because they cannot use the salvage pathway of nucleotide synthesis to supplement, where as most other cells can.
