BMS 545 Immunology Past Paper PDF

WELCOME- BMS 545 IMMUNOLOGY NOVEMBER 18, 2024  THE REST OF THE SEMESTER (ALL MODULE 4)  11/18- Transplantation & Immune Pharmacotherapy  (TBH, probably mostly secondary immunodeficiency).  11/20- Transplantation & Begin Cancer  11/22- Cancer & Tumor Immunity  11/25- Hypersensitivity (A...

WELCOME- BMS 545 IMMUNOLOGY NOVEMBER 18, 2024  THE REST OF THE SEMESTER (ALL MODULE 4)  11/18- Transplantation & Immune Pharmacotherapy  (TBH, probably mostly secondary immunodeficiency).  11/20- Transplantation & Begin Cancer  11/22- Cancer & Tumor Immunity  11/25- Hypersensitivity (Asynchronous- Enjoy Thanksgiving break)  11/27-11/29-Thanksgiving break  12/2- Autoimmune Disorders  12/4- “What’s Wrong with Me?” Case Study  12/6- Final Immunology debrief: The Well Patient  https://www.youtube.com/watch?v=qcZKbjYyOfE WHY SHOULD YOU CARE?  LEARNING OBJECTIVES  How are transplants classified? What are the different types? What do they mean?  What are the laws of transplantation?  Describe the premise of blood transfusion and blood antigens  What is direct vs. indirect recognition?  Compare and contrast direct & indirect allorecognition  Describe the types of hypersensitivity reactions seen with each type of transplant rejection/response  Compare & contrast the three types of rejection (hyperacute, acute, chronic)  Give examples of tissue specific complications (i.e. blood vs. solid organ) & sources of transplant material  Identify measures that alter the immune response to prepare for transplant, examples (e.g. CD52, etc.), and how they work  Compare & contrast the types of rejection vs. GvHD Chapter Opener Blood is the most commonly transplanted tissue  TYPES OF TRANSPLANTS (GRAFTS)  May be categorized by location or genetic relationship between recipient & donor 1. Location:  Orthotopic grafts- tissues or organs that are placed in their normal anatomic location  Heterotopic grafts- grafts that are placed into a site other than their normal  Especially useful when orthotopic placement may be technically difficult 2. Classification by donor–recipient genetic relationship is more complex:  Autografts- transferred from one part of an individual to another location on same individual  Syngeneic grafts (or isograft)- transferred between different individuals who are genetically identical or nearly so (e.g., identical twins or members of an inbred strain)  Allogeneic grafts (or allografts)- transferred between two genetically disparate individuals of same species (e.g., brother & sister, parent & child, or unrelated individuals)  Xenogeneic grafts (or xenografts)- exchanged between members of different species (e.g., placement of primate hearts into human recipients)  THE LAWS OF TRANSPLANTATION  The laws of transplantation can be summarized as follows: A host can recognize as foreign and mount a response against any histocompatibility antigen not encoded within its own cells  The outcomes of most types of tissue & organ transplantation are greatly improved if donor & recipient have similar tissue types  Donor & recipient are described as being histocompatible  Histocompatibility- describes two individuals with the same or near-identical HLA types & so will not mount strong immune rejection reactions against each others’ tissues  Allogeneic transplantation can trigger hypersensitivity reactions 15-2 Incompatibility of blood group antigens causes type II hypersensitivity reactions Figure 15.1 Structures of the ABO blood group antigens  ABO antigens are components of glycolipids present on erythrocyte surface  Core structure: lipid ceramide attached to an oligosaccharide consisting of glucose (Glu), galactose (Gal), N-acetyl galactosamine (GalNAc), galactose, & fucose (Fuc)  This glycolipid is present in all individuals  O individuals only have this core glycolipid  A individuals have 2 nd glycolipid (A antigen) with added GalNAc  B individuals have 2 nd glycolipid (B antigen) with added Gal Figure 15.2 In blood transfusion, donors and recipients must be matched for the ABO system of blood group antigens  Four groups of ABO antigens: O, A, B, & AB  Individuals have antibodies against A & B antigens that they lack (‘Recipient’ column on left)  Green boxes = donor & recipient blood type are compatible  Red boxes = donor & recipient blood type are incompatible  Incompatible would cause an antibody-mediated immune reaction Figure 15.3 Matching the ABO and Rhesus erythrocyte alloantigens in blood transfusion  Many different erythrocyte antigens, but clinically important ones are ABO & Rhesus D (RhD) antigens  O is NOT alloantigenic because everyone has it  O– RhD– people lack all 3 antigens (A, B, & Rhesus D) & are ‘universal donors’ who can provide a transfusion to any other person, but can only receive blood from other O– RhD– donors  AB RhD+ people have all three antigens & are ‘universal recipients’ who can receive blood from any donor, but can donate only to other AB RhD+ donors Green boxes show compatible  Bottom line= frequency of 8 blood types in the US population  Allogeneic transplantation can trigger hypersensitivity reactions 15-3 Hyperacute rejection of transplanted organs is a type II hypersensitivity reaction caused by preexisting antibodies binding to the graft  Before transplantation, some recipients have preexisting antibodies that react with donor ABO or HLA class I antigens  If donor organ is grafted into that recipient, antibodies bind immediately to vascular endothelium, initiating complement & clotting cascades  Blood vessels in graft become obstructed by clots & leak blood into graft  Graft becomes engorged, turns purple from presence of deoxygenated blood, & dies  In this case (L), kidney is surgically removed, & patient goes back on dialysis  Allogeneic transplantation can trigger hypersensitivity reactions 15-4 Anti-HLA antibodies arise from pregnancy, blood transfusion, & transplantation Pregnancy is the natural situation that leads to production of anti-HLA antibodies  Top: mothers & fathers (typically) have different HLA types  Center: after person becomes pregnant, they carry a fetus that expresses 1 maternal HLA haplotype (pink) & 1 paternal HLA haplotype (blue)  During pregnancy mother doesn’t respond to paternal HLA class I & class II expressed in fetus, because circulations are separate  Bottom: during trauma accompanying childbirth, cells from child gain access to maternal circulation & stimulate an immune response to paternally inherited HLA allotypes Allogeneic transplantation can trigger hypersensitivity reactions 15-5 Acute transplant rejection and graft-versus-host disease are type IV hypersensitivity reactions Alloreactions in transplant rejection & graft-versus-host disease  Left: Acute rejection of a transplanted organ occurs when recipient makes an immune response against allogeneic tissue & it can’t be controlled with immunosuppressive drugs  Right: graft-versus-host disease (GVHD) occurs when T cells in transplanted bone marrow attack the tissues (mainly skin, liver, & intestines) of recipient  Transplantation of solid organs 15-6 Organ transplantation involves procedures that produce inflammation in the donated organ and the transplant recipient  Transplantation of solid organs 15-7 HLA differences between transplant donor and recipient activate numerous alloreactive T cells All human TCR repertoires contain numerous T cells that recognize non-self MHC & have potential to make an alloreactive response  Top: represents unselected T-cell receptor repertoire of thymocytes  2nd & 3rd: show effects on this repertoire of positive & negative selection in thymus, which produce a T-cell population (red) that responds to foreign antigens presented by self MHC  Because there is no negative selection in thymus for non-self MHC, the repertoire of circulating T cells contains numerous alloreactive T cells, & many of them have affinities for allogeneic MHC that are higher than their affinity for self MHC Figure 15.8 The mixed lymphocyte reaction is a cellular test of histocompatibility Blood lymphocytes, monocytes, & dendritic cells are isolated from a patient seeking a kidney graft (blue) & from a possible kidney donor (yellow)  Donor’s cells are irradiated so that they act only as stimulators & not as responders (top)  Patient’s & donor’s cells are cultured together for 5 days  During this time, alloreactive T cells of patient are activated by allogeneic HLA class I & class II molecules of the donor  After 3 or 4 days of culture, proliferation of differentiating T cells is measured (bottom left)  Proliferation measures magnitude of alloreactive response  After 5 days of culture, capacity of effector CD8 T cells to kill donor cells is assessed (bottom right)  Killing of donor cells measures capacity for graft rejection  Transplantation of solid organs 15-8 Acute rejection is a type IV hypersensitivity caused by T cells responding to HLA differences between donor and recipient  Gross appearance of an acutely rejected kidney  Rejected graft is swollen & has deep-red areas of hemorrhage & gray areas of necrotic tissue Figure 15.11 Acute rejection of a kidney graft through the direct pathway of allorecognition  1st: donor dendritic cells in graft bear complexes of donor HLA molecules & peptides on surfaces  2nd: dendritic cells travel to spleen, where they move to T-cell areas where they activate the recipient’s alloreactive T lymphocytes (yellow)  3rd: after activation, effector T cells travel in blood to grafted organ, where they attack cells that express complexes of peptide & either HLA class I or HLA class II recognized by their TCRs  4th: transplant rejection  Transplantation of solid organs 15-9 Chronic rejection of transplanted organs is equivalent to a type III hypersensitivity reaction  Left: chronic rejection is caused by complexes of HLA & HLA-specific antibodies that deposit in blood vessels of transplanted kidney  Immune complexes bound to endothelial cells (E) recruit Fc receptor–bearing monocytes (Mo), neutrophils, & granulocytes (G)  Right: accumulating damage leads to EL thickening & infiltration of the underlying intima with SMCs, macrophages (Ma), alloreactive T cells, & antibodies  This narrows blood vessel lumen & creates chronic inflammation that intensifies tissue repair leading to EL, internal elastic lamina; SMC, smooth muscle cells; T, alloreactive T cell obstructed, ischemic, & fibrotic vessels Figure 15.13 Direct and indirect pathways of allorecognition contribute to graft rejection Dendritic cells from an organ graft stimulate both direct & indirect pathways of allorecognition when they travel from graft to draining lymphoid tissue  Left: in direct allorecognition, allogeneic HLA class I & class II of donor type on a donor dendritic cell (donor DC) interact directly with TCRs of recipient’s alloreactive CD4 & CD8 T cells  Right: death of a donor DC produces membrane vesicles containing allogeneic HLA class I & class II, which are endocytosed by recipient’s dendritic cells (recipient DC)  Peptides derived from donor’s HLA (yellow) are presented by recipient’s HLA (orange) to peptide-specific T cells (indirect allorecognition)  Peptides derived from donor HLA class I are Presentation by HLA class II to CD4 T cells is shown here presented by recipient HLA class I molecules to CD8 T cells (not shown) DIRECT VS. INDIRECT ALLORECOGNITION  Direct pathway of allorecognition- type of alloreactive response in which T cells of the recipient of a transplant are activated by direct interaction of their receptors with the allogeneic HLA molecules expressed by dendritic cells from the donor, and present in the transplant  Indirect pathway of allorecognition- one means by which alloreactive T cells in a transplant recipient can be stimulated to react against the transplant.The alloreactive T cells do not directly recognize the transplanted cells but recognize subcellular material from these cells that has been processed and presented by the recipient’s own dendritic cells Figure 15.14 The indirect pathway of allorecognition is responsible for stimulating the production of the anti-HLA antibodies that cause chronic graft rejection Processing & presentation of allogeneic HLA class I by a dendritic cell (DC) of recipient is shown  Dendritic cell activates helper CD4 T cells, which in turn activate B cells that have bound & internalized allogeneic donor HLA molecules  Shown here is a cognate interaction that leads to production of an anti- HLA class I alloantibody  Anti-HLA class II alloantibodies can be produced similarly  Because activated endothelium expresses both HLA class I & class II, antibodies against both classes of HLA molecule can contribute to chronic rejection  TYPES OF REJECTION (SUMMARY- WE COVERED THESE ABOVE)  Rejection responses fall into three general categories depending on timing and intensity 1. Chronic rejections- slowest & least vigorous type of rejection  Transplanted tissues or organs establish a vascular connection & proceed to function for weeks, months, & even years before signs of deterioration due to immune attack become evident  After 1st signs of rejection, graft destruction proceeds slowly & gradually as graft tissue is replaced by intracellular matrix & scar tissue  Typical in situations where donor & recipient differ by only non-MHC histocompatibility gene differences (*exceptions) 2. Acute rejections- occur much sooner after graft emplacement than chronic  Grafts establish vascular connections & function normally for a relatively short period (e.g., 2-4 weeks) before 1st signs of rejection  Unlike chronic, acute proceed rapidly once started  Grafts become edematous & inflamed, with an influx of blood & mononuclear cell infiltrates, & complete destruction & sloughing of grafted tissues may only take a few days following 1 st signs  Commonly seen when donor & recipient differ at MHC histocompatibility genes, especially involving MHC class I loci  TYPES OF REJECTION (SUMMARY- WE COVERED THESE ABOVE) 3. Hyperacute rejections- most rapid type of rejection  Initiated & completed within a few days of graft placement, usually before grafted tissue or organs can establish connections with recipient vasculature  Immune attack typically directed at vasculature of graft & is mediated by complement, natural killer (NK) cells, &/or preexisting antibodies  Aka “white grafts” because with skin, failure to establish a vascular connection gives engrafted skin a blanched appearance  Misleading; doesn’t describe comparable condition of other rejected tissues  Rejected kidney, for example, may be bluish in color due to large amount of deteriorating blood trapped inside  Like responses to infectious organs, immune responses against transplanted tissues or organs can display memory  Attempts to repeat grafts previously rejected usually results in accelerated graft rejection (second set rejection)  Grafts rejected chronically initially, may be rejected acutely when repeated  During initial rejection, activated T & B cells generate memory cells that create accelerated secondary responses  Second set responses= secondary immune responses directed against histocompatibility antigens  Transplantation of solid organs 15-10 Matching donor and recipient HLA class I and class II allotypes improves the outcome of kidney transplantation Colored lines represent the actual (to 5 years) & projected survival rates of kidney grafts in patients with no (blue), 1 (orange), 2 (red), 3 (dark blue), 4 (green), 5 (black), & 6 (brown) HLA mismatches, plotted on a semi-logarithmic scale.  Transplantation of solid organs 15-11 Immunosuppressive drugs enable allogeneic kidney transplantation to be a routine therapy 15-12 Immunosuppression is given before and after kidney transplantation  Anti-CD52 is efficient at fixing complement on leukocyte surfaces & triggering phagocytosis  This property is attributed to small size of CD52 (smaller than IgG & C3b)  On binding CD52, anti-CD52 is brought close to cell surface, increasing likelihood that C3b produced by complement activation will bind to leukocyte surface Figure 15.17 Steroids change patterns of gene transcription  Corticosteroids- lipid-soluble compounds that diffuse across plasma membrane & bind to their receptors in cytosol & modulate transcription of a wide variety of genes  Binding of corticosteroid to receptor displaces heat-shock protein Hsp90, exposing DNA- binding region of receptor, which then enters nucleus & binds to specific DNA sequences in promoter regions of steroid-responsive genes Figure 15.18 Effects of corticosteroids on the immune system  Corticosteroids alter expression of many genes to achieve anti-inflammatory effects 1. Reduce production of inflammatory mediators, including some cytokines, prostaglandins, & nitric oxide (NO)  By their effects on other cytokines, corticosteroids also decrease synthesis of IL-2 by activated lymphocytes 2. Prevent inflammatory cell migration to sites of inflammation by inhibiting expression of adhesion molecules 3. Promote apoptotic death of leukocytes & lymphocytes NOS, nitric oxide synthase.  Transplantation of solid organs 15-13 T-cell activation by alloantigens can be specifically prevented by immunosuppressive drugs Figure 15.19 Cyclosporin and tacrolimus inhibit T-cell activation by interfering with the serine/threonine phosphatase calcineurin  Signaling via tyrosine kinases associated with TCRs leads to activation of transcription factor AP-1 (left panels)  Ca2+ binds to calcineurin, thereby activating it to dephosphorylate cytoplasmic form of nuclear factor of activated T cells (NFAT)  Once dephosphorylated, active NFAT migrates to nucleus to form a complex with AP-1  The NFAT:AP-1 complex then induces transcription of genes required for T-cell activation, including gene encoding IL-2  Cyclosporin & tacrolimus interfere with activation of AP-1 (right panels)  Cyclosporin binds to cyclophilin & tacrolimus binds to FK-binding protein (FKBP)  Complex of cyclophilin with cyclosporin binds to calcineurin, blocking its ability to activate NFAT  Complex of tacrolimus with FKBP binds to calcineurin at same site, blocking its activity Figure 15.19 Cyclosporin and tacrolimus inhibit T-cell activation by interfering with the serine/threonine phosphatase calcineurin (Part 1) Bigger versions of the previous slide’s pic I’m leaving up in case you need to read it better Figure 15.19 Cyclosporin and tacrolimus inhibit T-cell activation by interfering with the serine/threonine phosphatase calcineurin (Part 2) Bigger versions of the previous slide’s pic I’m leaving up in case you need to read it better Figure 15.20 Immunological effects of cyclosporin and tacrolimus Figure 15.21 Acute rejection in a kidney graft  Shows lymphocytes around an arteriole (A) in a kidney undergoing rejection  Shows lymphocytes surrounding the renal tubules (T) of same kidney  Shows staining T lymphocytes with anti-CD3 (brown staining) in same section Figure 15.22 Serum sickness is a classic example of a type III hypersensitivity reaction  Upper left: an injection of large amount of antigenic protein (yellow curve) into circulation leads to a primary immune response with antibody production (red curve).Antibodies form immune complexes with antigen (blue-shaded area)  An:Ab complexes are deposited in small blood vessels & activate complement & phagocytes, inducing fever & symptoms of vasculitis, nephritis, & arthritis (lower left)  Effects are transient & resolve once antigen has been cleared  Photographs show hemorrhage in skin (upper panel) & urticarial rash (lower panel) resulting from serum sickness  Serum sickness- extreme form of type III hypersensitivity reaction that can occur when therapeutic amounts of a foreign protein are injected IV  Transplantation of solid organs 15-14 Blocking cytokine signaling prevents the activation of alloreactive T cells 15-15 Cytotoxic drugs target the replication and proliferation of activated alloreactive T cells  CD25 is not part of the low-affinity IL-2 receptor of naive alloreactive T cells (top) but is the α chain of high-affinity IL-2 receptor of alloreactive T cells that have been activated by signals 1 & 2  On binding to high-affinity IL-2 receptor, anti-CD25 prevents binding of IL-2 to receptor (bottom)  This prevents generation of signal 3 & interferes with further activation, proliferation, & differentiation of T cells  Anti-CD25 antibodies used clinically are chimeric basiliximab and humanized daclizumab  Transplantation of solid organs 15-16 Patients needing a transplant outnumber the available organs Patients who are eligible for a transplant have to wait ~2–3 years in the US or UK before they receive the transplant #s of waiting patients, transplants carried out, & donors in the US for the years 1991–2017 for all types of transplant are shown Figure 15.26 The supply of cadaveric donor organs is greater in countries where opting out of donation requires effort than in countries where opting in requires effort Figure 15.27 Frequency of solid organ transplantation throughout the world  Transplantation of solid organs 15-17 The need for HLA matching and immunosuppressive therapy varies with the organ transplanted For example, corneal allografts from cadaveric donors do not require assessment of HLA type & no administration of immunosuppressive drugs due to naturally immunosuppressive environment in anterior chamber of eye & lack of blood vessels in cornea Figure 15.28 A successful corneal allograft Figure 15.30 Hematopoietic cell transplantation is a therapy for genetic and malignant diseases of hematopoietic cells  Patient’s diseased hematopoietic system is destroyed by chemotherapy & irradiation  An infusion of hematopoietic stem cells obtained from a healthy HLA-matched donor is then given  Over a period of months, hematopoietic stem cells in graft reconstitute patient with a healthy hematopoietic system  Hematopoietic cell transplantation 15-18 Hematopoietic cell transplantation is a treatment for genetic diseases of blood cells As well as diseases listed here, bone marrow transplantation is a therapy for many genetically determined immunodeficiencies, such as SCID Figure 15.32 In a hematopoietic cell transplant the donor and recipient must share some HLA class I and class II molecules to reconstitute T-cell function (Part 1) After bone marrow transplantation, donor-derived thymocytes are positively selected on HLA allotypes expressed by recipient’s thymic epithelium  Show the hypothetical situation in which none of recipient’s HLA allotypes (red) are the same as donor’s HLA allotypes (blue)  In this situation, the recipient could not reconstitute a working T-cell system and would suffer from severe combined immune deficiency Figure 15.32 In a hematopoietic cell transplant the donor and recipient must share some HLA class I and class II molecules to reconstitute T-cell function (Part 2) After bone marrow transplantation, donor-derived thymocytes are positively selected on HLA allotypes expressed by recipient’s thymic epithelium  Show the situation when recipient & donor share the HLA allotypes indicated by blue  In clinical practice, bone marrow transplant donors & recipients are chosen to share as many HLA class I & class II allotypes as possible  Hematopoietic cell transplantation 15-19 Allogeneic hematopoietic cell transplantation is the preferred treatment for many cancers  Hematopoietic cell transplantation 15-20 After hematopoietic cell transplantation, the patient is attacked by alloreactive T cells in the graft (GvHD)  After bone marrow transplantation, any mature donor CD4 & CD8 T cells present in graft that are specific for recipient’s HLA allotypes become activated in secondary lymphoid tissues  Effector CD4 & CD8 T cells move into circulation & preferentially enter & attack tissues that have been most damaged by conditioning regimen of chemotherapy & irradiation: skin, intestines, & liver Figure 15.35 Characteristics of the four grades of graft-versus-host disease *Severe GVHD is defined as grades III & IV  Hematopoietic cell transplantation 15-21 HLA matching of donor and recipient is most important for hematopoietic cell transplantation  Two parameters of clinical outcome are shown: survival of patient (left panel) & incidence of severe GVHD (right panel)  An ‘allele match’ means that donor & recipient have identical HLA-A, -B, -C, & -DR alleles  A single mismatch means that donor & recipient differ by one HLA class I or class II allele  Transplants with class I & class II mismatch have one mismatched allele for HLA class I & one for class II  Fewer the mismatches, better survival & health of transplanted patient  Hematopoietic cell transplantation 15-22 Minor histocompatibility antigens activate alloreactive T cells in recipients of HLA-identical transplants The minor histocompatibility H-Y antigens are diverse & expressed only by males  For each peptide antigen listed here, its amino acid sequence, HLA class I or class II molecule that presents it (HLA restriction), & gene encoding protein are shown  Where known, amino acid substitutions that distinguish H- Y antigen (upper letters) from homologous sequence encoded by X chromosome (lower letters) are indicated  The H-Y antigens presented by A*01 & A*02 have an additional cysteine that forms a disulfide bond with cysteine indicated by C+ in peptide sequence  Hematopoietic cell transplantation 15-23 Some GVHD helps engraftment and prevents relapse of malignant disease 15-24 NK cells mediate graft-versus-leukemia effects Figure 15.38 Most patients who need a hematopoietic cell transplant have an HLA-haploidentical family member who is willing to be the donor Figure 15.40 Alloreactive NK cells can provide a graft-versus-leukemia effect in patients receiving a haploidentical hematopoietic cell transplant  Left panel: the HLA class I genotypes of the donor and the recipient, a patient with acute myelogenous leukemia. The key difference is that the donor has C1 (asparagine 80) and C2 (lysine 80) whereas the recipient has C2 and C4 (both lysine 80). Center panel: the NK cells of donor genotype that emerge after transplantation divide into two groups according to whether they are inhibited by C2 interacting with KIR2DL1 or by C1 interacting with KIR2DL3. Right panel: the recipient’s hematopoietic cells, including residual leukemia cells, inhibit only the first group of NK cells and not the second group.The latter kill the residual leukemia cells.  Hematopoietic cell transplantation 15-25 Hematopoietic cell transplantation can induce tolerance of a solid organ transplant  For example, dizygotic twins who had a common blood circulation during gestation are tolerant of each other’s tissues  Stimulation index is derived from mixed lymphocyte reactions in which lymphocytes from each twin were stimulated by lymphocytes from their sibling & from an unrelated control  Neither twin responds to their sibling, but both respond strongly to control lymphocytes