Ch. 17 Book Questions Transplant Immunology Flashcards
Experiments with inbred strains of mice have provided much of our knowledge of transplantation immunology. All mice of one inbred strain are genetically identical to one another and homozygous for all genes. Assume that strains A and B are inbred strains that differ from each other at all MHC gene loci but at no other loci. A mating of a strain A mouse with a strain B mouse (AxB) yields AxB F1 progeny. Which of the following skin grafts would NOT be rejected?
a. AxB F1 donor to A recipient
b. AxB F1 donor to B recipient
c. A donor to AxB F1 recipient
d. B donor to A recipient
e. A donor to B recipient
c. A donor to AxB F1 recipient
MHC molecules are responsible for almost all strong rejection reactions. The offspring of a mating between two different inbred strains will typically not reject grafts from either parent because all the MHC alleles of both parents are inherited by the offspring, and therefore their products are seen as self. Thus, an AxB recipient will not reject grafts from an A or B donor. However, a graft derived from an AxB F1 animal will be rejected by either an A or a B parent, because half the MHC gene products in the graft are foreign to either A or B strains. A or B recipients will reject grafts from B or A donors, respectively, because of MCH disparities.
All of the following statements regarding the direct presentation of alloantigens during transplant rejection are true EXCEPT:
a. Processing of allogeneic MHC molecules is not required for T cell recognition
b. A high percentage (~2%) of a graft recipient’s T cells are capable of directly recognizing the MHC molecules encoded by a single non-self MHC allele
c. All the different MHC molecules expressed on a graft cell can potentially be directly recognized by recipient T cells, even if they carry different peptides in the peptide binding clefts
d. In direct presentation, peptide bound to the foreign MHC molecule is not involved in TCR recognition
e. Memory T cells can be involved in direct recognition of allogeneic MHC molecules, even if the recipient has never been exposed to the donor MHC molecules before
d. In direct presentation, peptide bound to the foreign MHC molecule is not involved in TCR recognition
The direct presentation of allogeneic MHC molecules involves a cross-reaction of a T cell receptor selected to recognize self-MHC with a bound nonself peptide. This can occur because an allogeneic MHC molecule with a bound peptide can mimic the structures formed by self-MHC with bound foreign peptides. Peptides bound to allo-MHC contribute to the direct pathway of presentation in two ways. First, peptides are required for assembly and surface expression of MHC molecules. Second, peptides from graft cells may contribute to the structure seen by the recipient’s alloreactive T cells, even if they are from nonpolymorphic proteins found in the recipient. In such cases, it is the combination of the peptide and polymorphic residues of the MHC molecule that is recognized. As many as 2% of an individual’s T cells are capable of directly recognizing a single foreign MHC molecule, and such a high frequency of reactive T cells helps to engender a strong immune response. In addition, all of the MHC molecules on an allogeneic antigen-presenting cell are foreign to a recipient and therefore can be recognized by T cells, contributing to a strong rejection response. Many of these alloreactive T cells are memory T cells that were generated during previous exposure to other foreign antigens, hence making the initial response to alloantigens stronger and faster than primary immune responses to foreign microbes.
Which of the following best describes indirect presentation of allogeneic MHC molecules?
a. Donor allogeneic MHC molecules are shed from graft cells, inserted into recipient antigen presenting cells, loaded with recipient peptides, and presented to recipient T cells
b. Donor allogeneic MHC molecules are taken up by recipient antigen presenting cells, processed into peptides, and the peptides are presented on recipient MHC molecules to recipient T cells, similar to processing and presentation of microbial proteins
c. Donor allogeneic MHC molecules are taken up by recipient antigen presenting cells, processed into peptides, and the peptides are presented on recipient MHC molecules to donor T cells
d. Donor allogeneic MHC molecules are taken up by donor antigen presenting cells, processed into peptides, and the peptides are presented on unprocessed donor allogeneic MHC molecules to recipient T cells
e. Recipient MHC molecules are taken up by donor antigen presenting cells, processed into peptides, and the peptides are presented on donor allogeneic MHC molecules to recipient T cells
b. Donor allogeneic MHC molecules are taken up by recipient antigen presenting cells, processed into peptides, and the peptides are presented on recipient MHC molecules to recipient T cells, similar to processing and presentation of microbial proteins
In the indirect pathway, donor MHC molecules are processed and presented by recipient antigen-presenting cells (APCs) in the same manner that foreign protein antigens are presented in conventional immune responses to foreign antigens. Recipient T ells that recognize the peptides derived from the allogeneic MHC molecules in complex with self MHC proteins respond and mediate graft rejection. There is no mechanism by which intact allogeneic MHC molecules from donor cells can be inserted into host antigen presenting cells. Although it is possible that peptides derived from either donor or recipient MHC molecules may be loaded onto donor MHC molecules in donor antigen presenting cells, recognition of these complexes would be a form of direct recognition of allogeneic MHC, since intact donor MHC is being presented along with the peptide.
A 48 year old mother of two children with a history of post-streptococcal glomerulonephritis and chronic renal failure has been undergoing various tests in preparation for a possible kidney transplant. Among the first tests done was ABO blood typing. It was determined she was Type A. Which antibodies does she have circulating in her blood?
a. IgM specific for Group A antigen
b. IgG specific for Group B antigens
c. IgM specific for Group B antigen
d. IgG specific for Group A antigen
e. IgB specific for Group B antigen
c. IgM specific for Group B antigen
Blood group antigens are multimeric glycolipid antigens, not proteins, and therefore the antibodies against these antigens are largely IgMs. Type A individuals will only make anti-B antibodies and will be tolerant to Group A antigen, since the blood group antigens are ubiquitously expressed on many cell types and developing B cells will see group A antigens and be tolerized. Similarly, type B individuals will only make anti-A antibodies, type AB individuals will not make anti-A or anti-B, and type O individuals will make both anti-A and anti-B antibodies. The reason individuals make antibodies against the blood groups antigens that they do not produce is because gut flora produce the same or similar molecules, and early during life. Mature B1 cells are exposed to these antigens and are activated and differentiate into antibody secreting cells that produce the anti-blood group IgM antibodies.
Serum is taken from a patient waiting for a potential kidney donor and is used in a Panel Reactive Antibody (PRA) test, to detect the presence of antibodies specific for different HLA molecules. In this flow cytometry based test, the presence of serum antibodies specific for MHC molecules is analyzed by using different colored microbeads with different MHC proteins bound to each type of bead. The results indicated that she did have antibodies in her serum that bound to certain class I and class II MHC proteins on the beads. Which of the following is most likely true about those MHC proteins?
a. They are encoded by MHC alleles that her children inherited from their parents
b. They are encoded by MHC alleles that she inherited from her mother
c. They are encoded by MHC alleles that she inherited from her father
d. They are not encoded by MHC alleles inherited by either parent
e. They are encoded by MHC alleles present in both the patient and her children’s father
a. They are encoded by MHC alleles that her children inherited from their parents
In order for the patient to have anti-HLA antibodies, she must have been exposed to allogeneic MHC molecules in the past. The most common way this happens is pregnancy, during which time the mother is exposed to fetal cells that express MHC molecules encoded by genes inherited from the father and mother. Other ways an individual may be exposed to allogeneic MHC and therefore have circulating antibodies specific for these molecules are by prior blood transfusion or transplantation. The patient will not react to the MHC proteins encoded by the alleles she inherited from her parents, because these are her own, and are seen as self by her immune system.
If a patient received a kidney transplant from a donor who expressed MHC proteins or blood group antigens recognized by antibodies in the patient’s circulation at the time of transplantation, what problem is likely to arise due to these antibodies?
a. Hyperacute rejection within minutes
b. Chronic graft arterial disease within years
c. Acute rejection developing in several days
d. Opportunistic infections
e. Blistering skin disease
a. Hyperacute rejection within minutes
Hyperacute rejection is caused by preformed antibodies in a graft recipient that can bind to alloantigens expressed on the endothelial cells of vascularized grafts. These antibodies are present due to prior exposure to the alloantigens (see Question 4). The antibodies will activate complement on the endothelial cells of the graft, leading to thrombosis of the blood vessels, and rapid ischemic death of the graft. Acute and chronic graft rejection are due to active immunization of the recipient by donor alloantigens, and are not mediated by preformed antibodies. A graft recipient may be susceptible to opportunist infections due to immunosuppression, but this is not related to preformed antibodies. The patient’s skin will not be affected by antibodies that recognize alloantigens only present in the donor kidney.
A renal allograft recipient was given immunosuppressive drugs to prevent rejection. One of these drugs was a calcineurin inhibitor, called cyclosporin. Which of the following sequences best describes the signaling pathway that cyclosporine blocks?
a. IL2 Receptor …JAK1 …Ca++… Calcineurin…STAT5
b. TLR …MYD88… Calcineurin…IκB Kinase …NFκB
c. TCR… PLCγ1 …IP3… Ca++ …Calcineurin… NFAT
d. TLR… K+ … Calcineurin…TRIF…IRF3
e. TGFβ… Calcineurin… SMAD 3 …SMAD4
c. TCR… PLCγ1 …IP3… Ca++ …Calcineurin… NFAT
Calcineurin is a serine/threonine phosphatase that removes a phosphate residue on cytosolic NFAT, allowing translocation to the nucleus and induction of transcription of genes required for T cell proliferation, including genes encoding IL-2 and the high affinity IL-2 receptor chain CD25. Calcineruin inhibitors, such as cyclosporine or tacrolimus, will therefore inhibit T cell responses against alloantigens, and prevent graft rejection. The increased Ca++ that leads to calcinuerin activation is induced by TCR signaling which leads to activation of phsopholipase Cγ 1 (PLCγ1), which generates inositol trisphosphate (IP3) , which stimulates the release of Ca++stores from the endoplasmic reticulum. The placement of calcineurin in the other signaling pathways listed is incorrect.
Although differences in MHC proteins between graft donors and recipients is the underlying cause of immunological graft rejection, matching MHC alleles between donor and recipient is not of critical importance for success of transplantation of most organs and tissues, because of the efficacy of immunosuppressive drugs. Which of the following is the exception, where MHC matching is necessary for successful transplantation?
a. Liver
b. Kidney
c. Lung
d. Heart
e. Bone marrow
e. Bone marrow
Perhaps because of the high expression of MHC molecules, including class II MHC, on hematopoietic cells, bone marrow donors and recipient must be carefully matched to permit successful engraftment and reduce risk of graft vs. host disease. Usually donors are chosen who are completely matched with the recipient at the HLA-A, -B and -DR loci
