The economic implications of HLA matching in cadaveric renal transplantation.

Abstract Background: The potential economic effects of the allocation of cadaveric kidneys on the basis of tissue-matching criteria are controversial. We analyzed the economic costs associated with the transplantation of cadaveric kidneys with various numbers of HLA mismatches and examined the potential economic benefits of a local, as compared with a national, system designed to minimize HLA mismatches between donor and recipient in first cadaveric renal transplantations. Methods: All data were supplied by the U.S. Renal Data System. Data on all payments made by Medicare from 1991 through 1997 for the care of recipients of a first cadaveric renal transplant were analyzed according to the number of HLA-A, B, and DR mismatches between donor and recipient and the duration of cold ischemia before transplantation. Results: Average Medicare payments for renal-transplant recipients in the three years after transplantation increased from $60,436 per patient for fully HLA-matched kidneys (those with no HLA-A, B, or DR mismatches) to$80,807 for kidneys with six HLA mismatches between donor and recipient, a difference of 34 percent (P\u3c0.001). By three years after transplantation, the average Medicare payments were $64,119 for transplantations of kidneys with less than 12 hours of cold-ischemia time and$74,997 for those with more than 36 hours (P\u3c0.001). In simulations, the assignment of cadaveric kidneys to recipients by a method that minimized HLA mismatching within a local geographic area (i.e., within one of the approximately 50 organ-procurement organizations, which cover widely varying geographic areas) produced the largest cost savings ($4,290 per patient over a period of three years) and the largest improvements in the graft-survival rate (2.3 percent) when the potential costs of longer cold-ischemia time were considered. Conclusions: Transplantation of better-matched cadaveric kidneys could have substantial economic advantages. In our simulations, HLA-based allocation of kidneys at the local level produced the largest estimated cost savings, when the duration of cold ischemia was taken into account. No additional savings were estimated to result from a national allocation program, because the additional costs of longer cold-ischemia time were greater than the advantages of optimizing HLA matching

Mechanisms of chronic cardiac allograft rejection

Chronic rejection in the form of cardiac allograft vasculopathy is one of the major factors that affects long-term graft and patient survival after heart transplantation. Whereas multiple factors contribute to the development of cardiac allograft vasculopathy, immunologic mechanisms play the predominant role in the chronic rejection process, because both alloimmune and autoimmune responses are causal factors. In addition, many nonimmune donor and recipient factors also affect the development of cardiac allograft vasculopathy, including hyperlipidemia, cytomegalovirus infection, baseline coronary artery disease, and the mechanism of brain death in the donor. Modern immunosuppression maintenance therapies have the potential to limit the development of cardiac allograft vasculopathy in the long term. Further research initiatives are needed to identify patient-specific immunosuppressive drug regimens and to elucidate factors that contribute to the chronic rejection of cardiac transplant allografts

Effect of development of antibodies to hla and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome

AbstractObjective: A retrospective analysis was performed to examine the role of HLA antibodies and cytomegalovirus mismatch on the development of bronchiolitis obliterans syndrome and survival after lung transplantation. Methods: Of 339 consecutive lung transplantations performed over a 102-month interval, 301 patients survived at least 3 months. There was a minimum follow-up period of 13 months. Bronchiolitis obliterans syndrome was defined as a decline in forced expiratory volume in 1 second less than 80% of posttransplantation baseline and/or histologic presence of obliterative bronchiolitis and was defined as occurring “early” if documented within 3 years of transplantation. Variables analyzed included preoperative donor and recipient cytomegalovirus status and the development of antibodies to human leukocyte antigens after transplantation. Microcytotoxicity was used to determine the presence of antibodies to human leukocyte antigens. Variables were subjected to Kaplan-Meier analysis to determine their impact on freedom from bronchiolitis obliterans syndrome and survival. Results: The development of antibodies to human leukocyte antigens after transplantation correlated significantly with bronchiolitis obliterans syndrome (P = .02). The development of antibodies to human leukocyte antigens did not affect survival (P = .33) unless they were detected within 2 years of transplantation (P = .04). There was greater frequency of early bronchiolitis obliterans syndrome in cytomegalovirus seronegative patients who received allografts from seropositive donors compared with all other combinations (P = .02). There was also a trend toward worse survival of cytomegalovirus seronegative patients who received allografts from seropositive donors (P = .13). Conclusion: These data suggest that bronchiolitis obliterans syndrome is the result of an immune-mediated process in which HLA antibodies and cytomegalovirus may play a significant role. (J Thorac Cardiovasc Surg 1998;116:812-20

Neutrophil extracellular trap fragments stimulate innate immune responses that prevent lung transplant tolerance

Neutrophil extracellular traps (NETs) have been shown to worsen acute pulmonary injury including after lung transplantation. The breakdown of NETs by DNAse-1 can help restore lung function, but whether there is an impact on allograft tolerance remains less clear. Using intravital 2-photon microscopy, we analyzed the effects of DNAse-1 on NETs in mouse orthotopic lung allografts damaged by ischemia-reperfusion injury. Although DNAse-1 treatment rapidly degrades intragraft NETs, the consequential release of NET fragments induces prolonged interactions between infiltrating CD4 + T cells and donor-derived antigen presenting cells. DNAse-1 generated NET fragments also promote human alveolar macrophage inflammatory cytokine production and prime dendritic cells for alloantigen-specific CD4 + T cell proliferation through activating toll-like receptor (TLR) — Myeloid Differentiation Primary Response 88 (MyD88) signaling pathways. Furthermore, and in contrast to allograft recipients with a deficiency in NET generation due to a neutrophil-specific ablation of Protein Arginine Deiminase 4 (PAD4), DNAse-1 administration to wild-type recipients promotes the recognition of allo- and self-antigens and prevents immunosuppression-mediated lung allograft acceptance through a MyD88-dependent pathway. Taken together, these data show that the rapid catalytic release of NET fragments promotes innate immune responses that prevent lung transplant tolerance. © 2018 The American Society of Transplantation and the American Society of Transplant Surgeon

Extracellular vesicles: a potential new player in antibody-mediated rejection in lung allograft recipients

Identification of recipients with pre-existing antibodies and cross-matching of recipient sera with donor lymphocytes have reduced the incidence of antibody-mediated rejection (AMR) after human lung transplantation. However, AMR is still common and requires not only immediate intervention but also has long-term consequences including an increased risk of chronic lung allograft dysfunction (CLAD). The mechanisms resulting in AMR remain largely unknown due to the variation in clinical and histopathological features among lung transplant recipients; however, several reports have demonstrated a strong association between the development of antibodies against mismatched donor human leucocyte antigens [donor-specific antibodies (DSAs)] and AMR. In addition, the development of antibodies against lung self-antigens (K alpha1 tubulin and collagen V) also plays a vital role in AMR pathogenesis, either alone or in combination with DSAs. In the current article, we will review the existing literature regarding the association of DSAs with AMR, along with clinical diagnostic features and current treatment options for AMR. We will also discuss the role of extracellular vesicles (EVs) in the immune-related pathogenesis of AMR, which can lead to CLAD

Identification and translational validation of novel mammaglobin-A CD8 T cell epitopes

Mammaglobin-A (MAM-A) is a secretory protein that is overexpressed in 80% of human breast cancers. Its near-universal expression in breast cancer as well as its exquisite tissue specificity makes it an attractive target for a breast cancer prevention vaccine, and we recently initiated a phase 1 clinical trial of a MAM-A DNA vaccine. Previously, we have identified multiple MAM-A CD8 T cell epitopes using a reverse immunology candidate epitope approach based on predicted binding, but to date no attempt has been made to identify epitopes using an unbiased approach. In this study, we used human T cells primed in vitro with autologous dendritic cells expressing MAM-A to systematically identify MAM-A CD8 T cell epitopes. Using this unbiased approach, we identified three novel HLA-A2-restricted MAM-A epitopes. CD8 T cells specific for these epitopes are able to recognize and lyse human breast cancer cells in a MAM-A-specific, HLA-A2-dependent fashion. HLA-A2+/MAM-A+ breast cancer patients have an increased prevalence of CD8 T cells specific for these novel MAM-A epitopes, and vaccination with a MAM-A DNA vaccine significantly increases the number of these CD8 T cells. The identification and translational validation of novel MAM-A epitopes has important implications for the ongoing clinical development of vaccine strategies targeting MAM-A. The novel MAM-A epitopes represent attractive targets for epitope-based vaccination strategies, and can also be used to monitor immune responses. Taken together these studies provide additional support for MAM-A as an important therapeutic target for the prevention and treatment of breast cancer

Hepatitis C virus-induced changes in microRNA 107 (miRNA-107) and miRNA-449a modulate CCL2 by targeting the interleukin-6 receptor complex in hepatitis

Hepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBPα, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBPα, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBPα. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA-449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis. IMPORTANCE Hepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics

Immune Responses to Tissue-Restricted Nonmajor Histocompatibility Complex Antigens in Allograft Rejection

Chronic diseases that result in end-stage organ damage cause inflammation, which can reveal sequestered self-antigens (SAgs) in that organ and trigger autoimmunity. The thymus gland deletes self-reactive T-cells against ubiquitously expressed SAgs, while regulatory mechanisms in the periphery control immune responses to tissue-restricted SAgs. It is now established that T-cells reactive to SAgs present in certain organs (e.g., lungs, pancreas, and intestine) are incompletely eliminated, and the dysregulation of peripheral immuneregulation can generate immune responses to SAgs. Therefore, chronic diseases can activate self-reactive lymphocytes, inducing tissue-restricted autoimmunity. During organ transplantation, donor lymphocytes are tested against recipient serum (i.e., cross-matching) to detect antibodies (Abs) against donor human leukocyte antigens, which has been shown to reduce Ab-mediated hyperacute rejection. However, primary allograft dysfunction and rejection still occur frequently. Because donor lymphocytes do not express tissue-restricted SAgs, preexisting Abs against SAgs are undetectable during conventional cross-matching. Preexisting and de novo immune responses to tissue-restricted SAgs (i.e., autoimmunity) play a major role in rejection. In this review, we discuss the evidence that supports autoimmunity as a contributor to rejection. Testing for preexisting and de novo immune responses to tissue-restricted SAgs and treatment based on immune responses after organ transplantation may improve short- and long-term outcomes after transplantation