Podcast
Questions and Answers
What primarily causes the rejection of transplanted organs?
What is the outcome when cells or organs are transplanted between genetically identical individuals?
How does the offspring of a mating between two different inbred strains of animals respond to grafts?
What happens if skin from unrelated donors is used to replace skin on burn patients?
Signup and view all the answers
What is a unique aspect of HSC transplantation compared to other types of grafts?
Signup and view all the answers
What is the characteristic of memory and specificity linked to?
Signup and view all the answers
What typically occurs during the transplantation between genetically nonidentical individuals?
Signup and view all the answers
What term best describes an inflammatory reaction leading to graft failure?
Signup and view all the answers
What is the main outcome of negative selection in T lymphocyte maturation?
Signup and view all the answers
Which of the following is NOT a reason for cell death during T lymphocyte maturation?
Signup and view all the answers
What are the three class I MHC genes in humans?
Signup and view all the answers
Which process describes T cells recognizing intact, unprocessed MHC molecules?
Signup and view all the answers
What is the location of the human MHC genes in terms of chromosome and size?
Signup and view all the answers
What are the components of class II MHC molecules composed of?
Signup and view all the answers
Which of the following improves the presentation of peptides to T cells in an individual?
Signup and view all the answers
What is the term for the set of MHC alleles present on each chromosome?
Signup and view all the answers
What does indirect presentation of graft MHC molecules imply?
Signup and view all the answers
How is the structure of the allogeneic MHC molecule recognized by alloreactive T cells?
Signup and view all the answers
What initiates the T cell response to an organ graft?
Signup and view all the answers
In the context of direct MHC allorecognition, which T cell types are involved?
Signup and view all the answers
What role do resident APCs in transplanted organs play in T cell activation?
Signup and view all the answers
What happens to host DCs after they migrate into the graft?
Signup and view all the answers
Why do allogeneic MHC molecules appear structurally different from self MHC molecules?
Signup and view all the answers
What is the process by which recipient T cells recognize graft MHC molecules?
Signup and view all the answers
Which type of rejection is characterized by thrombotic occlusion of the graft vasculature within minutes to hours after surgery?
Signup and view all the answers
What is the principal mechanism involved in acute cellular rejection of a graft?
Signup and view all the answers
What role do alloantibodies play in acute antibody mediated rejection?
Signup and view all the answers
Which of the following best describes the dominant lesion of chronic rejection in vascularized grafts?
Signup and view all the answers
Which cells are primarily responsible for the production of cytokines leading to inflammation during acute cellular rejection?
Signup and view all the answers
What is graft vasculopathy associated with in the context of failed organ transplants?
Signup and view all the answers
Which of the following factors is a common trigger for chronic graft rejection?
Signup and view all the answers
How does the binding of alloantibodies to endothelial cells affect the graft?
Signup and view all the answers
What is the primary purpose of hematopoietic stem cell (HSC) transplantation?
Signup and view all the answers
What complication arises from the reaction of grafted mature T cells in HSC transplantation?
Signup and view all the answers
How are induced pluripotent stem (iPS) cells advantageous compared to embryonic stem cells?
Signup and view all the answers
What is a common susceptibility faced by HSC transplant recipients?
Signup and view all the answers
What genetic method is being investigated to avoid rejection of allogeneic embryonic stem cells?
Signup and view all the answers
What type of infections are HSC transplant recipients particularly prone to due to immunosuppression?
Signup and view all the answers
What is a critical factor for the successful acceptance of allogeneic HSCs in transplantation?
Signup and view all the answers
What type of lymphomas can be provoked in HSC transplant recipients due to viral infection?
Signup and view all the answers
Study Notes
Transplant Rejection
- Graft rejection is an inflammatory response caused by an adaptive immune response.
- Grafts between genetically identical individuals (identical twins or members of the same inbred strain) are not rejected.
- Grafts between genetically nonidentical individuals (different people or members of different inbred strains) are almost always rejected.
- The offspring of a mating between two different inbred strains will not reject grafts from either parent.
- A graft derived from the offspring of a mating between two different inbred strains will be rejected by either parent.
T Lymphocyte Maturation in the Thymus
- Negative selection eliminates developing lymphocytes that bind strongly to self-antigens.
- Negative selection is caused by:
- Failure to productively rearrange the TCR β chain gene.
- Failure to be positively selected by self MHC molecules.
- Self antigen-induced negative selection.
MHC Genes
- Polymorphic class I and class II MHC molecules are responsible for displaying peptide antigens for recognition by CD8+ and CD4+ T cells.
- Different MHC alleles bind and display different peptides.
- Individuals express alleles inherited from both parents.
Map Of The Human MHC Genes
- The MHC is located on the short arm of chromosome 6 and spans 3500 kilobases (kb).
- There are three Class I MHC genes (HLA-A, HLA-B, and HLA-C) that encode three types of class I MHC molecules.
- There are three class II HLA gene loci (HLA-DP, HLA-DQ, and HLA-DR).
- Each class II MHC molecule consists of a heterodimer of α and β polypeptides.
- An MHC haplotype is the set of MHC alleles present on each chromosome.
Direct and Indirect Alloantigen Recognition
- Allogeneic MHC molecules can be presented for recognition by recipient T cells in two ways: direct and indirect.
- Direct presentation is the recognition of intact, unprocessed MHC molecules in the graft.
- Indirect presentation occurs when the recipient's MHC molecules present peptides derived from the donor MHC proteins to recipient T cells.
Molecular basis of direct recognition of allogeneic MHC molecules
- MHC molecules on cell surfaces normally contain bound peptides, which contributes to the structure recognized by the alloreactive T cell.
- Although these peptides may be derived from proteins common to the donor and recipient, they are displayed by allogeneic MHC molecules on the graft cells.
- Complexes of peptides with allogeneic MHC molecules appear different from self peptide-self MHC complexes.
- Direct recognition and activation of an alloreactive T cell can occur regardless of the peptide carried by the allogeneic MHC molecule if the polymorphic amino acid residues of the allogeneic MHC molecule resemble self MHC plus peptide.
Activation of alloreactive T cells
- T cells respond to an organ graft in the lymph nodes that drain the graft.
- Transplanted organs contain resident APCs (such as DCs) that express donor MHC molecules.
- Donor APCs migrate to regional lymph nodes and present unprocessed allogeneic MHC molecules to recipient CD8+ and CD4+ T cells (direct MHC allorecognition).
- Host DCs can migrate into the graft, pick up graft alloantigens, and transport them to the draining lymph nodes for presentation (indirect pathway).
Hyperacute Rejection
- Hyperacute rejection occurs within minutes to hours after blood vessel anastomosis.
- It is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens and cause thrombotic occlusion of the graft vasculature.
Acute Cellular Rejection
- Acute cellular rejection is caused by CTL-mediated killing of graft parenchymal cells and endothelial cells, along with inflammation caused by cytokines produced by helper T cells.
Acute Antibody-Mediated Rejection
- Alloantibodies cause acute rejection by binding to alloantigens (mainly HLA molecules) on vascular endothelial cells, leading to endothelial injury and intravascular thrombosis.
- Alloantibody binding triggers local complement activation, resulting in cell lysis, neutrophil recruitment and activation, and thrombus formation.
- Alloantibodies can engage Fc receptors on neutrophils and NK cells, killing endothelial cells.
- Alloantibody binding can directly alter endothelial function by inducing proinflammatory and procoagulant molecules.
Chronic Rejection
- A dominant lesion of chronic rejection in vascularized grafts is arterial occlusion due to intimal smooth muscle cell proliferation.
- The arterial changes are called graft vasculopathy or accelerated graft arteriosclerosis.
- Graft vasculopathy is common in failed cardiac and renal allografts and can develop within 6 months to a year after transplantation.
- Mechanisms underlying occlusive vascular lesions include activation of alloreactive T cells and secretion of IFN-γ and other cytokines that stimulate vascular smooth muscle cell proliferation.
Immunologic Complications of Hematopoietic Stem Cell Transplantation
- HSC transplantation is used to treat lethal diseases caused by defects in hematopoietic lineages.
- HSCs from a healthy donor are given to restore normal blood cell production.
- Allogeneic HSCs are rejected by even a minimally immunocompetent host, so donor and recipient must be carefully matched at all MHC loci.
- GVHD is caused by the reaction of grafted mature T cells with host alloantigens.
- Immunodeficiency after HSC transplantation makes recipients susceptible to viral (especially CMV), bacterial, and fungal infections.
- Recipients are also susceptible to Epstein-Barr virus-provoked B cell lymphomas.
### Induced Pluripotent Stem (iPS) cells
- Pluripotent stem cells can be used to repair tissues with limited regenerative capacity.
- Embryonic stem cells will likely be rejected due to their alloantigenicity.
- iPS cells, derived from adult somatic tissues by gene transduction, can be derived from the patient's own cells and therefore will not be rejected.
- Removing MHC genes from allogeneic embryonic stem cells using CRISPR-Cas9 genome editing technology is another solution being investigated.
Generation of Chimeric Antigen Receptor Regulatory T Cells (CAR Tregs)
- CAR Tregs are being explored for their potential to suppress immune responses to organ grafts and reduce the need for immunosuppressive drugs.
Genetic Modifications in Pigs for Pig-to-Human Organ Transplantation
- Pigs have been genetically modified to reduce the risk of immune rejection in xenotransplantation (organ transplantation between different species).
- Modifications include removing or silencing genes responsible for producing antigens that trigger human immune responses, such as α-1,3-galactosyltransferase.
- Enhancing expression of genes that suppress immune responses, such as CD46, is another strategy.
- These modifications aim to improve the safety and efficacy of pig organs as potential sources for transplantation in humans.
Studying That Suits You
Use AI to generate personalized quizzes and flashcards to suit your learning preferences.
Related Documents
Description
This quiz covers key concepts surrounding transplant rejection, the role of T lymphocyte maturation in the thymus, and the importance of MHC genes in the immune response. Test your understanding of these critical aspects of immunology and their implications for graft acceptance and rejection.
