RESUMEN
Alessandro Moretta was Professor of Histology at University of Brescia from 1994 to 1997. It was in that period that we met and started a collaboration that continued in the years to follow. He immediately involved us in the production of monoclonal antibodies (mAbs) that allowed the identification and fine characterization of novel receptor molecules that were able to activate or inhibit human Natural Killer cell function, including several antibodies specific for Natural Cytotoxicity Receptor (NCR) and Killer-cell Immunoglobulin-like Receptor (KIR) molecules. These reagents, generated in our laboratory in Brescia, contributed to complete the studies aimed to characterize innate lymphoid NK cells, that had been initiated by Alessandro and his brother Lorenzo in Genoa. Soon, we identified an anti-KIR3DL2 that was subsequently shown to be helpful for the diagnosis and treatment of various forms of cutaneous T cell lymphoma. While in Brescia, Alessandro established a partnership with those of us who were working in the Department of Pediatrics; together, in short time we tackled the goal of studying the role of NK cells in patients with primary immunodeficiencies. This collaboration led to novel discoveries that shed light on the critical role played by NK cells in the immune response against virus and tumors in humans, as best exemplified by our characterization of the molecular mechanisms of impaired control of Epstein-Barr Virus (EBV) infection in patients with X-linked lymphoproliferative (XLP) disease. After Alessandro left Brescia to return to Genoa, our collaboration continued with the same enthusiasm, and even from a distance he remained an extraordinary example of an inspirational and generous mentor. This review is a sign of our gratitude to a mentor and a friend whom we deeply miss.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Células Asesinas Naturales/inmunología , Trastornos Linfoproliferativos , Enfermedades de Inmunodeficiencia Primaria , Receptores KIR , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/historia , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/inmunología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/historia , Trastornos Linfoproliferativos/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/historia , Enfermedades de Inmunodeficiencia Primaria/inmunología , Receptores KIR/genética , Receptores KIR/historia , Receptores KIR/inmunologíaRESUMEN
Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different with different prognoses and responsiveness to therapy, resulting in 2 different malignancies. We attempted to confirm reports suggesting that the relative frequency of these 2 histologies is shifting over time. We analyzed 3040 adult PTLD cases in the UNOS OPTN database from 1999 to 2013. Changes in PTLD cases over time were analyzed for histology, time from transplant to diagnosis, and patient EBV serostatus. We found that the relative proportion of polymorphic versus monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; P = <.001). The change is driven by a gradual increase in the number of monomorphic PTLD with a steady number of polymorphic PTLD. The change is most strongly seen in transplant recipients who were EBV serostatus positive at the time of transplant. Potential causes are changes in immunosuppressive regimens with increased tacrolimus use (P = .009) and increased survival among transplant patients leading to later occurrence of PTLD (P = .001) that have occurred during the time frame analyzed. As organ transplantation has evolved over time, PTLD has coevolved. These changes in histology have important implications regarding the origin and clinical management of PTLD.
Asunto(s)
Trastornos Linfoproliferativos/etiología , Trasplante de Órganos/efectos adversos , Adolescente , Adulto , Infecciones por Virus de Epstein-Barr/diagnóstico , Femenino , Histología/tendencias , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Trastornos Linfoproliferativos/historia , Trastornos Linfoproliferativos/virología , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenAsunto(s)
Biopsia con Aguja Fina/métodos , Trastornos Linfoproliferativos/diagnóstico , Tripanosomiasis/diagnóstico , Colorantes Azulados/historia , Biopsia con Aguja Fina/historia , Biopsia con Aguja Fina/instrumentación , Eosina Amarillenta-(YS)/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Trastornos Linfoproliferativos/historia , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/cirugía , Guías de Práctica Clínica como Asunto , Tripanosomiasis/historia , Tripanosomiasis/patología , Tripanosomiasis/cirugíaAsunto(s)
Lupus Eritematoso Sistémico/historia , Enfermedades Linfáticas/historia , Trastornos Linfoproliferativos/historia , Receptor fas/historia , Animales , Apoptosis , Historia del Siglo XX , Lupus Eritematoso Sistémico/inmunología , Enfermedades Linfáticas/inmunología , Trastornos Linfoproliferativos/inmunología , Ratones , Mutación , Receptor fas/genética , Receptor fas/inmunologíaRESUMEN
IgG4-related disease is a novel lymphoproliferative disorder that shows hyper-IgG4-γ-globulinemia and IgG4-producing plasma cell expansion in affected organs with fibrotic or sclerotic changes. Patients show systemic inflammatory conditions and various symptoms depending on the affected organ. Since the first report of patients with elevated serum IgG4 in sclerosing pancreatitis in 2001, various systemic disorders described by many names have been reported. Despite similarities in the organs involved in IgG4-related Mikulicz's disease and Sjögren's syndrome, there are marked clinical and pathological differences between these conditions. Most patients diagnosed with autoimmune pancreatitis in Japan have IgG4-related pancreatitis [Type 1 autoimmune pancreatitis (AIP), lymphoplasmacytic sclerosing pancreatitis (LPSP)], a disease distinct from some of the western type [Type 2 AIP, idiopathic duct-centric chronic pancreatitis (IDCP), autoimmune pancreatitis with granulocytic epithelial lesions (GEL)]. Diagnosis of IgG4-related disease is characterized by both elevated serum IgG4 (>135 mg/dL) and histopathological features including lymphocyte and IgG4(+) plasma cell infiltration (IgG4(+) plasma cells/IgG(+) plasma cells>40%). Differential diagnosis from other distinct disorders, such as sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, cancer, and other existing conditions associated with high serum IgG4 level or abundant IgG4-bearing plasma cells in tissues is necessary. We have begun a clinical prospective study to establish a treatment strategy (Phase II prospective treatment study for IgG4-multiorgan lymphoproliferative syndrome: UMIN R000002311).
Asunto(s)
Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Diagnóstico Diferencial , Historia del Siglo XXI , Humanos , Inmunoglobulina G , Japón , Trastornos Linfoproliferativos/historia , Enfermedad de Mikulicz/patología , Síndrome de Sjögren/patologíaRESUMEN
On the occasion of the first meeting of the Robert A. Good Immunology Society in June of 2006, I was asked to provide a perspective on the history and progress of the field of bone marrow transplantation. I was honored to provide this perspective at that meeting and subsequently in this manuscript. This review has a strong University of Minnesota bias, as Minneapolis is a place where important roots in this field were developed. Minnesota is also where I have spent my career in this field learning the excitement of laboratory research beginning as a medical student under Bob Good and Carlos Martinez in 1960, and clinical research in pediatrics under Bill Krivit and Mark Nesbit beginning in 1970. This review is dedicated to two of my recently deceased mentors: Bob Good was a pioneer in so many ways and a true giant in immunology and blood and marrow transplantation. Bill Krivit taught me a great deal about genetic diseases and the critical role of compassion and understanding patients and their families in dealing with fatal illness and new treatments such as bone marrow transplantation that are often risky and themselves may result in suffering and death. My affection for Bob Good and Bill Krivit is unending.
Asunto(s)
Transfusión Sanguínea/historia , Trasplante de Médula Ósea/historia , Enfermedad Injerto contra Huésped/historia , Neoplasias Hematológicas/historia , Síndromes de Inmunodeficiencia/historia , Trastornos Linfoproliferativos/historia , Animales , Transfusión Sanguínea/tendencias , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/tendencias , Enfermedad Injerto contra Huésped/terapia , Neoplasias Hematológicas/terapia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Síndromes de Inmunodeficiencia/terapia , Trastornos Linfoproliferativos/terapia , Ratones , Minnesota , Universidades/historiaRESUMEN
The aims of this study were to evaluate the clinical characteristics of HIV-negative patients affected by lymphoproliferative disorders (LPD) who developed progressive multifocal leukoencephalopathy (PML), to delineate the risk factors, and to analyze whether the new antineoplastic therapies are changing the natural history of this infectious disease. We retrospectively analyzed 46 cases with confirmed LPD-associated PML published from 1958 to 2004. Patients were stratified according to two different time periods: group A included patients diagnosed before 1989, and group B included patients diagnosed since 1990, after introduction of purine analogues. Group A patients (n = 22) had received alkylating agents and/or radiotherapy, and the majority (63.6%) had advanced Hodgkin disease. At univariate analysis, uncontrolled Hodgkin disease was the only risk factor for PML. In group B patients (n = 24), the most frequent treatments received were purine analogues (58.3%) and high-dose therapy with hematopoietic stem cell transplantation (33.3%; HDT/HSCT). B-cell chronic lymphocytic leukemia (45.8%) and aggressive non-Hodgkin lymphoma (24.9%) were the most frequent underlying LPDs. Patients treated with purine analogues were more likely to have active LPD, lower CD4 cell counts, and to be older and male than were HSCT recipients. The median interval from purine analogues or HDT/HSCT to PML was 11 months. In HDT/HSCT recipients, this interval was delayed for 10 months when peri-transplantation rituximab was used. Univariate analysis identified age >55 years, male sex, and CD4 cell counts Asunto(s)
VIH
, Leucoencefalopatía Multifocal Progresiva/terapia
, Trastornos Linfoproliferativos/terapia
, Adulto
, Factores de Edad
, Anciano
, Alquilantes/uso terapéutico
, Anticuerpos Monoclonales/uso terapéutico
, Anticuerpos Monoclonales de Origen Murino
, Antineoplásicos/uso terapéutico
, Recuento de Linfocito CD4
, Terapia Combinada/historia
, Terapia Combinada/métodos
, Supervivencia sin Enfermedad
, Femenino
, Historia del Siglo XX
, Historia del Siglo XXI
, Humanos
, Leucoencefalopatía Multifocal Progresiva/complicaciones
, Leucoencefalopatía Multifocal Progresiva/historia
, Leucoencefalopatía Multifocal Progresiva/mortalidad
, Trastornos Linfoproliferativos/complicaciones
, Trastornos Linfoproliferativos/historia
, Trastornos Linfoproliferativos/mortalidad
, Masculino
, Persona de Mediana Edad
, Pronóstico
, Purinas/uso terapéutico
, Radioterapia/historia
, Radioterapia/métodos
, Estudios Retrospectivos
, Factores de Riesgo
, Rituximab
, Factores Sexuales
, Trasplante de Células Madre/historia
, Trasplante de Células Madre/métodos
Asunto(s)
Anemia Hemolítica Autoinmune/historia , Hormona Adrenocorticotrópica/historia , Hormona Adrenocorticotrópica/uso terapéutico , Anemia Hemolítica Autoinmune/inmunología , Anemia Hemolítica Autoinmune/terapia , Especificidad de Anticuerpos , Antihipertensivos/efectos adversos , Antihipertensivos/historia , Autoanticuerpos/inmunología , Transfusión Sanguínea/historia , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/historia , Cortisona/historia , Cortisona/uso terapéutico , Eritrocitos/inmunología , Heparina/historia , Heparina/uso terapéutico , Historia del Siglo XX , Humanos , Inmunosupresores/historia , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/historia , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/historia , Metildopa/efectos adversos , Metildopa/historia , EsplenectomíaRESUMEN
The X-linked lymphoproliferative disease (XLP), one of six described X-linked immunodeficiencies, stems from a mutation at Xq25 which renders males impotent to mount an effective immune response to the ubiquitous EBV. Purtilo, who first observed this disease in 1969, established a Registry in 1980 to serve as a worldwide resource for the diagnosis, treatment, and research of this condition. Since Purtilo's death in late 1992, the Registry and research unit have not only continued to function as a worldwide consultative service, but have contributed the following. First, the number of affected boys has continued to grow; some 272 among 80 kindreds have been identified. Second, some boys (10%) who inherit the mutated XLP gene are immunologically abnormal even before evidence of EBV exposure. Third, the search for the XLP gene has been narrowed to a small region on Xq25. Its identification is near at hand; once cloned, this gene may well illustrate how the body orchestrates the complex immune response to EBV. Therein lies the justification for the quest for this gene, not only for the benefit of the few surviving boys and those to be born to female carriers, but also for defining its role in defending the body against a ubiquitous DNA virus.