Solid Organ Transplant Flashcards
Examples of primary and secondary lymphatic tissue
Primary: Bone marrow and thymus
Secondary: Spleen, and lymph nodes
Which organ transplant type is the most common? Which transplant type has the most people waiting for that organ?
Kidney is the most common transplant performed and people waiting for a kidney has the largest amount of people waiting on the list
Explain why people may need a transplanted kidney? Heart? or liver?
Kidney: ESRD
Heart: Refractory heart failure, refractory ventricular arrhythmias and refractor angina
Liver: Alcohol induced liver disease and Hep C
What are the general contraindications to transplantation?
Those with a medical condition that would limit life expectancy after transplant. Including: Active cancer, active infections or other chronic life threatening diseases. Others include, inability to follow difficult medication regimen or active alcohol/substance abuse.
Explain the complement cascade
Several proteins sequentially activate other members of the cascade ultimately resulting in lysis of the foreign cell.
What are the 3 APCs? Explain them
Dendritic cells: Mostly located in skin and mucus membranes. Their role is to ingest material from their surroundings, hydrolytic ally digest proteins and present the resulting peptide fragment as antigens to T and B cells.
Macrophages: Ingest and process pathogens, cellular debris, necrotic cells and other components and displayed as antigens on their surface. Play role in inflammation process. (secrete cytokines). Most commonly found in the lungs, skin, liver, spleen and lymphatic system.
B-lymphocytes: Born in the bone marrow but take residency in secondary lymph organs until they are activated by foreign antigen binding to b cell receptor. Once activated, they grow and differentiate into memory or plasma cells which secrete antibodies against the antigen.
Explain the difference between HLA (MHC) I and II
Proteins that make up the MHC are called HLA.
HLA I is expressed on every cell with a nucleus and is responsible for displaying self antigens which allow immune system to identify and ignore their own cells.
HLA II specializes in presenting antigens which the cell internalizes during phagocytosis. Almost exclusively expressed by the 3 APCs.
Explain T cell maturation
T cells originate in the bone marrow and migrate to the thymus gland for maturation. Here they will differentiate into cytotoxic T cells or T helper cells. They are released into circulation where they take up residency in the lymphoid tissue.
Explain the maturation process of T cells as it relates to positive and negative selection. How are these 2 different?
Because each T cell receptor is different, these processes are necessary to select viable T cells for various roles.
Negative selection: Identifies TCRs that recognizes and binds to ANY HLA molecule expressing “self” antigen. It is important these cells stay localized to the thymus gland so they don’t attack healthy tissue. Basically, negative selection prevents devastating autoimmune response.
Positive selection: TCR must be able to recognize the 3D structure of foreign antigens and the HLA peptides that make up the HLA. This process ensures the maturation of T-cells can efficiently recognize HLA proteins.
Explain the immune recognition by cytotoxic T cells and helper T cells
Cytotoxic: Recognize HLA I because it interacts with CD8.
T helper: Recognize HLA II because it interacts with CD4.
Explain clonal expansion
CD3 complex ties the TCR to respective HLA molecules which initiates a signaling cascade that replicates the T cell and leads to a large pool of identical T cell that are capable of recognizing and eliciting an immune response against the same foreign antigen. Good in a normal person, bad in someone who just had an allograft because clonal expansion may lead to destruction of allograft.
Explain the role of Th cells
T helper cells do not directly kill the pathogen. They play a role in activating B cells which generate antibodies to the same antigen the Th cell recognizes.
Explain the nuclear factor of activated t cells (NF-AT)
NF-AT is a protein that must be dephosphorylated to allow entry into the nucleus. The enzyme responsible for removing the critical phosphate residue from NF-AT is calcineurin. Inhibiting this enzyme is one of the most effective ways to precent IL-2 mediated clonal expansion of activated T cells.
Explain the difference between direct and indirect pathways of immune response to a transplanted organ
Direct: Requires that the allograft is accompanied by donor APCs which have hitched a ride with transplanted tissue. Donor APCs will present donor antigens as both HLA I and II which will activate recipient Tc and Th cells which results in a full immune response against allograft.
Indirect: Recipient APCs present donor antigens in HLA type II which activate recipient Th and B cells which release antibodies against the allograft.
What is hyper acute rejection?
If the recipient has preexisting antibodies which recognize the allograft as foreign, the transplanted tissue will rapidly be attacked and can show signs of rejection within minutes. Uncommon to kidney and heart transplant and rare in liver.
What is acute cellular rejection?
Can occur anytime throughout the life of the allograft, most commonly observed within the first few months though. Occurs when activated Tc cells, recognize endothelial antigens or infiltrate the allograft and recognize the presentation of antigens within the parenchyma of the transplanted tissue.
What is humoral rejection?
Mediated by alloreactive antibodies that attacks the donor vasculature. Begins after the transplant has been completed.
What is chronic rejection?
Mimics a slow acting cellular and/or humoral response accompanied by persistent inflammation. NOT REVERSIBLE and will lead to loss of allograft. Pharmacotherapy cannot treat this type of rejection, but immunosuppressive therapy can slow this process.
Why is it recommended to give small doses of few medications compared to large doses of one medication?
Severe adverse effects and systemic toxicity. Lower doses of few drugs will have a more favorable side effect profile compared to large dose of one medication.
Which drugs inhibit calcineurin?
Cyclosporin A and tacrolimus
Which drugs inhibit mTOR?
Sirolimus, everolimus
Which drugs are antimetabolites?
Azathioprine and mycophenolate
Which glucocorticoids do we use to prevent allograft rejection?
Pred and methylpred
Which medication is a biologic?
Belatacept
List the 2 polyclonal antibodies
ATG, RATG
List the 3 monoclonal antibodies
Basiliximab, muromonab, aletuzumab
Explain why Neural and Sandimmune formulations of cyclosporin A are not interchangeable
Neural achieves slightly better but more consistent bioavailability than the sandimmune formulation.
