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Significance of HLA in Transfusion and Transplantation Terry Aly Clinical Pathology Conference February 8, 2008 Main Topics • HLA System Overview • HLA and Transfusion – Alloimmunization • Refractoriness to platelets • Graft rejection – Transfusion-Associated Graft-Versus-Host Disease (TA-GVHD) – Transfusion-Related Acute Lung Injury (TRALI) • HLA and Transplantation – Bone marrow – Cord blood – Solid organ The Human Leukocyte Antigen (HLA) System • Essential to immune function: HLA molecules present peptide antigens to the immune system (T-cells) • Important for self versus non-self distinction HLA Class I Monitors Inside of the Cell Tapasin CR CN Dr. Brian Freed HLA Class II Monitors Outside of Cell Peptides Extracellular Proteins DM monitors peptide specificity for DR DM Dr. Brian Freed HLA Class I and II Molecules Have a Distinct Structure and Function •Binds 8-10mers •Expressed on most Nucleated cells •Presents Cytosolic Proteins to CD8+ T cells •Binds 13-25mers •Expressed on APCs, Macs, B cells, activated T cells •Presents Vesicular Proteins to CD4+ T cells 2 3 Class I Class II BDC Antigen–presenting cells (APCs): monocytes, macrophages, dendritic cells, B cells Teaching slides: www.barbaradaviscenter.com Humoral Versus Cellular Immune Response Class I (1.1 Mb) Class III (0.7 Mb) Class II (2.2 Mb) Complement & cytokines Gene low high resolution typing “subtype”=01 Allele: Haplotype: Genotype: HLA-DRB1*0401 HLA-DRB1*0401 HLA-DQB1*0302 HLA-DRB1*0301 HLA-DQB1*0201 DRB1*02 HLA-DRB1*04 HLA-DQB1*0302 J. Noble Why care about HLA type for transfusions? • Alloimmunization with increased risk for platelet refractoriness and humoral transplant rejection – Recipient can make antibody against donor HLA antigen, most common • Transfusion-Related Acute Lung Injury – donor HLA antibodies react against recipient antigens • Transfusion-Associated Graft-Vs-Host Disease Alloimmunization • Alloimmunization: Development of antibodies after exposure to non-self human antigen – HLA on leukocytes or platelet specific antigens – May occur with transfusions (PRBC>platelet because PRBC contain more leukocytes), pregnancies, or transplants Antigen exposure associated with leukocytes in transfusion, pregnancy, or transplantation Alloimmunization Resolves Spontaneously (Transfusion Ab resolve more than pregnancy Ab) Refractoriness to platelets* Humoral transplant rejection *Antibodies can react with Class I HLA (most common), ABH antigens, or platelet antigens that exist on surface of platelets How to prevent alloimmunization? Trial to Reduce Alloimmunization to Platelets (TRAP) study • Leukoreduction (LR) effect – Removes 99.9% of leukocytes, leaving < 5*106 per unit – Only 19% of AML patients receiving leukoreduced platelets developed lymphocytotoxic antibodies vs. 45%* receiving unmodified platelets *alloimmunization rate likely higher: current methods detect more alloantibodies than previously The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med. 1997. How to prevent alloimmunization? • UV irradiation was equally effective in TRAP study (prevents lymphocytes from proliferating or stimulating), but blood banks typically use Gamma instead of UV b/c can penetrate plastic bags • LR or irradiation decreased alloimmunization from 13% to 3-4% in previously unexposed patients The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med. 1997. UVB-PC: UV B-irradiated, pooled platelet concentrates, random donors F-PC: Filtered pooled platelet concentrates, random donors F-AP: Filtered apheresis, single random donor 16% 10% 8% Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med. 1997. Who needs alloimmunization prevention? • Give LR or irradiated blood products to patients who are: – chronically transfused (20-70% become refractory) – immunoincompetent – pre- and post-transplant • All transplant patients? Include kidney? • Time-frame? – everyone?? Prestorage Universal Leukoreduction in Canada • Universal prestorage leukoreduction (ULR) of red cell and platelet products has been performed in Canada since August 1999 (and UK too) Seftel MD, Growe GH, Petraszko T, et al. Universal prestorage leukoreduction in Canada decreases platelet alloimmunization and refractoriness. Blood. 2004 Jan 1;103(1):333-9. Prestorage Universal Leukoreduction (ULR)—Canada study • Retrospective analysis of 13,902 platelet transfusions in 617 patients undergoing chemotherapy for ALL or stem cell transplantation before (n=315) and after (n=302) ULR instituted • Alloimmunization was significantly reduced (19% to 7%, P <.001) in the post-ULR group. • Alloimmune platelet refractoriness was similarly reduced (14% to 4%, P <.001). Prestorage Universal Leukoreduction (ULR)—UK study • ULR reduced TA-GVHD rate in immunocompetent individuals from 13 prior to ULR to 0 after ULR • ULR reduced post-transfusion purpura rate from 10.3 per year to 2.3 per year • Alloimmunization was significantly reduced (19% to 7%, P <.001) in the post-ULR group. • Alloimmune platelet refractoriness was similarly reduced (14% to 4%, P <.001). Refractoriness • Repeated failure to achieve the expected increment in platelet count after 2 or more platelet transfusions • % Maximum increment = ([pretransfusion count – posttransfusion count in platelets/µL] X blood volume in mL) ÷ (number of platelets transfused, ie, number of U X 6 X 105) Slichter SJ. Evidence-Based Platelet Transfusion Guidelines Hematology 2007 Refractoriness • Can be due to: • Alloimmunization to HLA or platelet antigen • ABO mismatch • Non-immune factors such as insufficient dosing, poor platelet quality, hypersplenism, accelerated consumption, sepsis, DIC, GVHD, and bleeding Slichter SJ. Evidence-Based Platelet Transfusion Guidelines Hematology 2007 Management of Refractoriness • Stage 1: Check dosing • Stage II: Try ABO matched platelets <48 hours old • Stage III: If urgent, give cross-matched platelets. Screen for anti-HLA and anti-platelet antibodies – Antibody-mediated or not? Solid-phase assay – HLA antibody mediated or not? Panel reactive antibody (PRA) as general screen for HLA Ab positivity. – If positive, single antigen testing with microparticle beads to ID which antigen(s) to avoid in donors Slichter SJ. Evidence-Based Platelet Transfusion Guidelines Hematology 2007 ABO matching prevents platelet refractoriness Table 1 -- Refractoriness and alloimmunization rates after transfusing ABO matched versus mismatched platelets New antibodies Platelet transfusions Enrolled Female patients Possible prior sensitization[a] Platelet transfusions[b] Platelet refractoriness[c] ABO matched 13 10 (77%) 9 (69%) 7 (5–9) 1 (8%) ABO mismatched 13 2 (15%) 4 (31%) 9 (4–30) 9 (69%) P value 0.001 Data from Carr R, Hutton JL, Jenkins JA, et al. Transfusion of ABO-mismatched platelets leads to early platelet refractoriness. Br J Haematol 1990;75:408–13 Anti A/B[d] 0 7 (54%) Anti-HLA Platelet-specific 1 (8%) 1 (8%) 5 (38%) 4 (31%) Problems with HLA Typing and Matching • HLA matching requires the availability of large numbers of HLA-typed donors. A registry of about 18 000–25 000 HLA-typed people is needed to provide at least five HLA-A and HLA-B matched donors for 80% of white patients. • HLA-matched platelets requires the recruitment of specific donors, such platelets can only be obtained by apheresis • Expensive K Takahashi, T Juji and H Miyazaki, Determination of an appropriate size of unrelated donor pool to be registered for HLA-matched platelet transfusion, Transfusion, 1987. Problem with cross-matching to find compatible platelets • Limited to units available for testing • 5 day life to platelets, future transfusions will require re-crossmatching Antibody Specificity Prediction The antibody specificity prediction (ASP) method of donor selection for refractory alloimmunized patients appears as effective as HLA matching or crossmatching. Far more donors are identified in a file of HLA-typed donors by the ASP method than by HLA matching, and this indicates that the ASP method provides important advantages regarding the availability of compatible platelet components. Percentage of platelet recovery is similar for HLA-matched, cross-matched, and antibody specificity prediction method matched donor platelets Petz LD. Selecting donors of platelets for refractory patients on the basis of HLA antibody specificity. Transfusion. 2000. PRA=panel reactive antibodies Cross-Reactive Groups • Systems have been developed to match donor and recipient by assigning HLA-A and HLA-B antigens with shared public epitopes to clusters called cross-reactive groups (CREGs). • When one or two mismatches of HLA-A or HLAB antigens in CREGs is permitted, a pool of 1000– 3000 donors will meet the transfusion needs of most white patients HLA Matchmaker • Based on the principle that short three-amino acid sequences characterize polymorphic sites of the HLA molecules, and are the critical components of allo-sensitizing epitopes • Retrospective study has shown that platelets selected with this algorithm result in higher posttransfusion count rises than those selected using traditional HLA matching strategies A Nambiar, RJ Duquesnoy and S Adams et al., HLAMatchmaker-driven analysis of responses to HLA-typed platelet transfusions in alloimmunized thrombocytopenic patients, Blood 107 (2006), pp. 1680–1687. Clinimmune • Testing available for: • Clinical Transplantation- solid organ and hematopoietic stem cell • Platelet Transfusion support Clinimmune • HLA-A, B, Cw, DRB, DQB1, DPB1 loci – Low to high resolution testing for HLA-A, B, Cw, DRB1,DRB3/4/5, DQB1 – Intermediate to high resolution testing for HLA-DPB1 – Serological and molecular testing • HLA Antibody Detection – PRA=Panel Reactive Antibody, including HLA Specificity Analysis • Luminex • ELISA • Complement Dependent Cytotoxicity, including AHG (anti-human globulin) – Titration/Quantitation studies for pre-transplant immunotherapy protocols – Crossmatching for transplant compatibility • Flow cytometry • Complement Dependent Cytotoxicity, including AHG (anti-human globulin) From Clinimmune website Other options to treat refractoriness? • For highly alloimmunized patients and those with rare HLA types, finding compatible platelets can be difficult. • Several immune-modulatory therapies tried: intravenous immune globulin; cyclosporin A; vinblastine; staphyloccal protein A; removal of HLA antigens with citric acid. • Despite anecdotal positive outcomes, these strategies are usually not successful or practical Transfusion-associated graft-vshost disease • Depends on – immune system function in recipient – lymphocytes in transfused component – degree of HLA similarity between donor and recipient • Donor lymphocytes not recognized as foreign if HLA similar • More common with related donors – Especially if donors homozygous for shared HLA haplotype with recipient Transfusion-associated graft-vshost disease • Caused by persistent chimerism after blood transfusion – Transfused lymphocytes avoid destruction by host immune system, proliferate, and attack host organs – Causes skin rash (histo “satellite dyskeratosis”), fever, liver dysfunction, diarrhea, bone marrow dysplasia – Occurs 4-30 days post-transfusion, >90% fatal – In 1980, incidence in patients with hematologic cancers or lymphoproliferative disorders 0.1-1%, now lower due to leukoreduction and irradiation; more rare if not immunocompromised www.up-to-date.com/TA-GVHD TA-GVHD more common in immunocompromised patients receiving directed donor HLA-matched products, but can occur in immunocompetent individuals and can be random donor with high HLA similiarity For example…… • Common “ancestral” haplotype –DR3, B8, A1 haplotype –In 9% of chromosomes in the Caucasian population, and 18% of chromosomes in Caucasians with diabetes (Alper 2006) –Diabetic population at risk for kidney transplantation Illumina 2: 24 DR3B8A1 (8.1) Homozygous Individuals Column=individual; Row=SNP; Yellow=Homozygous region for 8.1 alleles Gray=non-8.1 allele; White=8.1 allele; Dark Gray Bar=1st SNP homozygous for non-8.1 alleles telomere 25.2 Mb 7.6 Mb conserved HLA-F HLA-A DQB1 32.8 Mb A A B A B A B A B A B A A A A B B A B A A B B A B B B B A B B A A A A B B A B A B A B A B A B B A A A -A -A B B A B A -A B B A B A B B A B A -B -A B B A B A -B -A B B A B A B A A B A A A B A B B A A B A B A A B B A B B B B A B A B A B B A B A B A B A A B A B A B A B A A A B A A B B A A B A B A B A B A B B B A B B A B A A B B A B A B A B B A B A B B A A B A A A B A B A A B A A B A B A B A B B B B A A B A B A B B A B A B A B A B A B B --A A B A -A A B A A -B A A A B - A B B B --A A B A -A B B A B B A -B A -A B B - -A A B A B A B A -A -B A A B A B -A B A -A B A B - -B B B A B A -B B A B B -A B A B A B - A B A B B A B A A B A B A A A A B A A B A B A B B B A B A B B A B A B B A B A B A B A B A B A A B A A B A A A B A A A B B A B A B A B B A A B A A B B B B A B A B A B A B A B B A A B B A B A A B A B A A B B A B B B A B A B B A B B B B A B A B A B A B A B A B B A A A B A B A A B A B A A B B B A B A B B A A B B A B A A B A B A B A B A B A A A A A B A B A A B A A A B A B A B B A B B A A B B B B A B B A B A B A A B A A A B A A B A A A -A B A B A B A B B A B B A A B B A B B -B A B A B A B A B A B A B A A A A B A B A A B A B A B A B A B B A B A B B A B B B B B A B A B A A B A A A B A A B A A B A -B A A B B A B B A B A B A A B B A B B A B -B A A B B A B A B B A A A B A B A A B A B A B A B A B B B A B A B A B A B A B B B A B A B A A B A B A A A A B B A A B A A B A A B B B B B A B A B A B B A B A B A B A B A B A B A A A A A B A A B A A B A B A B B A B B A B A B B B A B B B A B A B A B A B A B B A A A B A B A B A A B A B A B A A B A B A B B A B A B A B B A B B A B A B A A B A B A B B A A B A A A B A A B A B A A B B A B A B B A B B A B B A B B A B A B B A B A B A B A B A A B A B A B A B A A B A B A A B B A B B B A B A A B B A B B A B A B A B B A B A B A A B A A A A B A A B A B A A B B A B B B B A B A B A B A B B B B A B A B A A A B A B A A A B A A B A B A A B A B A B A A B B B B A A B B A B B B B A B A B B A B A A A A A B A B A B A B A A B A B A A B B A B B B B A B A B B A B B A B B A B A B A Case study • 31 yo F receives kidney transplant from her father, matched for all but one antigen, DR7 • 2 wks later, she needs PRBC transfusion – Family wants her to receive directed donor transfusion from father • Should a directed donor transfusion from her father be permitted? • If so, should it be leukoreduced or irradiated? • If not, should a random donor blood product be leukoreduced or irradiated? • Should the guidelines for kidney transplant patients differ from those of heart, lung or bone marrow transplant patients? • What if patient is known to have one HLA antibody formed against transplant? Follow-up Information • Received directed donor routine PRBC given from father (not leukoreduced or irradiated) • Humoral transplant rejection diagnosed • PRA antibody negative prior to transfusion; DR7 antibody detected post-transfusion HLA and Transplantation Bone marrow • HLA class I and II matching High resolution • Aim for at least 9/10 HLA alleles matching HLA and Transplantation Cord Blood • Low resolution HLA class I match; highresolution class II HLA match • Safer than bone marrow transplant because cord blood induces less reaction • Aim for at least 4 out of 6 matching for transplantation HLA and Transplantation Solid organ • Lung: Class II HLA match • Heart: Class I HLA match on case-by-case basis, no class I • Liver: No HLA typing indicated • Kidney: Class I and II HLA matching but O.K if only 1 or 2 out of 6 matching HLA alleles because prognosis depends more on timing of transplant; prefer negative cross-matching strategy