RESUMEN
Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Adulto , Humanos , Interferón gamma , Linfocitos T CD8-positivos , Células Clonales/patología , Receptores de Antígenos de Linfocitos TAsunto(s)
Leucemia de Células Plasmáticas/patología , Antígenos de Neoplasias/análisis , Bortezomib/uso terapéutico , Diagnóstico Diferencial , Hemofiltración , Humanos , Cadenas lambda de Inmunoglobulina/análisis , Inmunofenotipificación , Leucemia de Células Plasmáticas/sangre , Leucemia de Células Plasmáticas/diagnóstico , Leucemia de Células Plasmáticas/terapia , Antígenos Comunes de Leucocito/análisis , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/diagnóstico , Paraproteínas/análisis , Sindecano-1/análisisRESUMEN
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.
Asunto(s)
Enfermedades Autoinmunes/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Síndromes de Inmunodeficiencia/genética , Corticoesteroides/uso terapéutico , Adulto , Enfermedades Autoinmunes/complicaciones , Colitis/complicaciones , Colitis/genética , Colitis/patología , Femenino , Fiebre/complicaciones , Fiebre/tratamiento farmacológico , Fiebre/genética , Haploinsuficiencia , Heterocigoto , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Linfopenia/complicaciones , Linfopenia/genética , Masculino , Persona de Mediana Edad , Mutación , Pancitopenia/complicaciones , Pancitopenia/tratamiento farmacológico , Pancitopenia/genética , Linaje , Polimorfismo de Nucleótido Simple , Recurrencia , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/diagnóstico por imagen , Infecciones del Sistema Respiratorio/genética , Esplenomegalia/complicaciones , Esplenomegalia/genética , Síndrome , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). A number of studies support a role for B cells in the pathogenesis of cGvHD. In this study, we report the presence of an expanded population of CD19+CD21- B cells with features of exhaustion in the peripheral blood of patients with cGvHD. CD21- B cells were significantly increased in patients with active cGvHD compared to patients without cGvHD and healthy controls (median 12.2 versus 2.12 versus 3%, respectively; p < 0.01). Compared with naïve (CD27-CD21+) and classical memory (CD27+CD21+) B cells, CD19+CD21- B cells in cGvHD were CD10 negative, CD27 negative and CD20hi, and exhibited features of exhaustion, including increased expression of multiple inhibitory receptors such as FCRL4, CD22, CD85J, and altered expression of chemokine and adhesion molecules such as CD11c, CXCR3, CCR7, and CD62L. Moreover, CD21- B cells in cGvHD patients were functionally exhausted and displayed poor proliferative response and calcium mobilization in response to B-cell receptor triggering and CD40 ligation. Finally, the frequencies of circulating CD21- B cells correlated with cGvHD severity in patients after HSCT. Our study further characterizes B cells in chronic cGVHD and supports the use of CD21-CD27-CD10- B cell frequencies as a biomarker of disease severity.
RESUMEN
The establishment of long-lived pathogen-specific T cells is a fundamental property of the adaptive immune response. However, the mechanisms underlying long-term persistence of antigen-specific CD4+ T cells are not well-defined. Here we identify a subset of memory CD4+ T cells capable of effluxing cellular toxins, including rhodamine (Rho), through the multidrug efflux protein MDR1 (also known as P-glycoprotein and ABCB1). Drug-effluxing CD4+ T cells were characterized as CD161+CD95+CD45RA-CD127hiCD28+CD25int cells with a distinct chemokine profile and a Th1-polarized pro-inflammatory phenotype. CD4+CD161+Rho-effluxing T cells proliferated vigorously in response to stimulation with anti-CD3/CD28 beads and gave rise to CD161- progeny in vitro. These cells were also capable of self-renewal and maintained their phenotypic and functional characteristics when cultured with homeostatic cytokines. Multidrug-effluxing CD4+CD161+ T cells were enriched within the viral-specific Th1 repertoire of healthy donors and patients with acute myeloid leukemia (AML) and survived exposure to daunorubicin chemotherapy in vitro. Multidrug-effluxing CD4+CD161+ T cells also resisted chemotherapy-induced cytotoxicity in vivo and underwent significant expansion in AML patients rendered lymphopenic after chemotherapy, contributing to the repopulation of anti-CMV immunity. Finally, after influenza vaccination, the proportion of influenza-specific CD4+ T cells coexpressing CD161 was significantly higher after 2 years compared with 4 weeks after immunization, suggesting CD161 is a marker for long-lived antigen-specific memory T cells. These findings suggest that CD4+CD161+ T cells with rapid efflux capacity contribute to the maintenance of viral-specific memory T cells. These data provide novel insights into mechanisms that preserve antiviral immunity in patients undergoing chemotherapy and have implications for the development of novel immunotherapeutic approaches.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Regulación Leucémica de la Expresión Génica , Memoria Inmunológica , Gripe Humana/prevención & control , Leucemia Mieloide Aguda/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/inmunología , Antibióticos Antineoplásicos/farmacología , Anticuerpos/farmacología , Transporte Biológico , Antígenos CD4/genética , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/clasificación , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/crecimiento & desarrollo , Citomegalovirus/inmunología , Daunorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Humanos , Inmunofenotipificación , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/inmunología , Gripe Humana/virología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/virología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/crecimiento & desarrollo , Orthomyxoviridae/inmunología , Rodaminas/metabolismo , Rodaminas/farmacología , Transducción de Señal , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/patologíaRESUMEN
Cord blood (CB) offers a number of advantages over other sources of hematopoietic stem cells, including a lower rate of chronic graft-versus-host disease (cGVHD) in the presence of increased HLA disparity. Recent research in experimental models of autoimmunity and in patients with autoimmune or alloimmune disorders has identified a functional group of interleukin-10 (IL-10)-producing regulatory B cells (Bregs) that negatively regulate T-cell immune responses. At present, however, there is no consensus on the phenotypic signature of Bregs, and their prevalence and functional characteristics in CB remain unclear. Here, we demonstrate that CB contains an abundance of B cells with immunoregulatory function. Bregs were identified in both the naive and transitional B-cell compartments and suppressed T-cell proliferation and effector function through IL-10 production as well as cell-to-cell contact involving CTLA-4. We further show that the suppressive capacity of CB-derived Bregs can be potentiated through CD40L signaling, suggesting that inflammatory environments may induce their function. Finally, there was robust recovery of IL-10-producing Bregs in patients after CB transplantation, to higher frequencies and absolute numbers than seen in the peripheral blood of healthy donors or in patients before transplant. The reconstituting Bregs showed strong in vitro suppressive activity against allogeneic CD4(+) T cells, but were deficient in patients with cGVHD. Together, these findings identify a rich source of Bregs and suggest a protective role for CB-derived Bregs against cGVHD development in CB recipients. This advance could propel the development of Breg-based strategies to prevent or ameliorate this posttransplant complication.
Asunto(s)
Linfocitos B Reguladores/inmunología , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Sangre Fetal/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Interleucina-10/metabolismo , Activación de Linfocitos/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Femenino , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal , Adulto JovenRESUMEN
A subset of regulatory B cells (Bregs) in mice negatively regulate T-cell immune responses through the secretion of regulatory cytokines such as IL-10 and direct cell-cell contact and have been linked to experimental models of autoimmunity, inflammation, and cancer. However, the regulatory function of Bregs in human disease is much less clear. Here we demonstrate that B cells with immunoregulatory properties are enriched within both the CD19(+)IgM(+)CD27(+) memory and CD19(+)CD24(hi)CD38(hi) transitional B-cell subsets in healthy human donors. Both subsets suppressed the proliferation and interferon-γ production of CD3/CD28-stimulated autologous CD4(+) T cells in a dose-dependent manner, and both relied on IL-10 secretion as well as cell-cell contact, likely mediated through CD80 and CD86, to support their full suppressive function. Moreover, after allogeneic stem cell transplantation, Bregs from patients with chronic graft-versus-host disease (cGVHD) were less frequent and less likely to produce IL-10 than were Bregs from healthy donors and patients without cGVHD. These findings suggest that Bregs may be involved in the pathogenesis of cGVHD and support future investigation of regulatory B cell-based therapy in the treatment of this disease.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B Reguladores/inmunología , Enfermedad Injerto contra Huésped/inmunología , Inmunoglobulina M/inmunología , Memoria Inmunológica , ADP-Ribosil Ciclasa 1/metabolismo , Antígenos CD19/metabolismo , Subgrupos de Linfocitos B/metabolismo , Linfocitos B Reguladores/metabolismo , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígeno CD24/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Estudios de Casos y Controles , Comunicación Celular , Células Cultivadas , Enfermedad Crónica , Citocinas/biosíntesis , Enfermedad Injerto contra Huésped/metabolismo , Humanos , Inmunomodulación , Inmunofenotipificación , Mediadores de Inflamación/metabolismo , Interleucina-10/biosíntesis , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis TumoralRESUMEN
The majority of patients with acute myeloid leukemia will relapse, and older patients often fail to achieve remission with induction chemotherapy. We explored the possibility that leukemic suppression of innate immunity might contribute to treatment failure. Natural killer cell phenotype and function was measured in 32 consecutive acute myeloid leukemia patients at presentation, including 12 achieving complete remission. Compared to 15 healthy age-matched controls, natural killer cells from acute myeloid leukemia patients were abnormal at presentation, with downregulation of the activating receptor NKp46 (P=0.007) and upregulation of the inhibitory receptor NKG2A (P=0.04). Natural killer cells from acute myeloid leukemia patients had impaired effector function against autologous blasts and K562 targets, with significantly reduced CD107a degranulation, TNF-α and IFN-γ production. Failure to achieve remission was associated with NKG2A overexpression and reduced TNF-α production. These phenotypic and functional abnormalities were partially restored in the 12 patients achieving remission. In vitro co-incubation of acute myeloid leukemia blasts with natural killer cells from healthy donors induced significant impairment in natural killer cell TNF-α and IFN-γ production (P=0.02 and P=0.01, respectively) against K562 targets and a trend to reduced CD107a degranulation (P=0.07). Under transwell conditions, the inhibitory effect of AML blasts on NK cytotoxicity and effector function was still present, and this inhibitory effect was primarily mediated by IL-10. These results suggest that acute myeloid leukemia blasts induce long-lasting changes in natural killer cells, impairing their effector function and reducing the competence of the innate immune system, favoring leukemia survival.
Asunto(s)
Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Técnicas de Cocultivo , Citocinas/metabolismo , Citotoxicidad Inmunológica , Femenino , Humanos , Inmunofenotipificación , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quimioterapia de Inducción , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Receptores de Células Asesinas Naturales/metabolismo , Inducción de Remisión , Insuficiencia del Tratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.
Asunto(s)
Antineoplásicos/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Adulto , Agammaglobulinemia Tirosina Quinasa , Anciano , Antineoplásicos/uso terapéutico , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Cambio de Clase de Inmunoglobulina/efectos de los fármacos , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Memoria Inmunológica/efectos de los fármacos , Vacunas contra la Influenza/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Fosfolipasa C gamma/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Vacunas Neumococicas/inmunología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismoAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Receptores KIR/genética , Tiazoles/uso terapéutico , Dasatinib , Humanos , Farmacogenética/métodos , Pronóstico , Receptores KIR/metabolismoRESUMEN
BACKGROUND: In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. DESIGN AND METHODS: We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49. RESULTS: By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P<0.001), 46% of allogeneic stem cell transplant recipients (P<0.001) and 85% of patients with chronic myeloid leukemia (P=0.086). After a second dose, seroprotection rates increased to 68%, (P=0.008), 73%, (P=0.031), and 95% (P=0.5) in patients with B-cell malignancies, after allogeneic stem cell transplantation and with chronic myeloid leukemia, respectively. On the other hand, T-cell responses to H1N1 vaccine were not significantly different between patients and controls. CONCLUSIONS: These data demonstrate the efficacy of H1N1 vaccine in most patients with hematologic malignancies and support the recommendation for the administration of two doses of vaccine in immunocompromised patients. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in such patients in the future.
Asunto(s)
Neoplasias Hematológicas/virología , Huésped Inmunocomprometido , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/inmunología , Vacunación/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Estudios de Casos y Controles , Femenino , Pruebas de Inhibición de Hemaglutinación , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/terapia , Humanos , Inmunidad Celular , Gripe Humana/complicaciones , Gripe Humana/prevención & control , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Trasplante de Células Madre , Tasa de Supervivencia , Adulto JovenRESUMEN
Limited data are available on immunologic responses to primary H1N1 infection in patients with hematologic malignancies. We present a prospective, case-surveillance study of such patients with real-time polymerase chain reaction (RT-PCR) confirmed H1N1-influenza who presented to our institution between September 2009 and January 2010. Ninety-two patients presented with influenza-like symptoms, and 13 had H1N1 infection confirmed by RT-PCR, including 4 allogeneic stem cell transplant recipients (1 with acute myelogenous leukemia, 1 with chronic lymphoblastic leukemia [CLL], 1 with non-Hodgkin lymphoma, and 1 with chronic myelogenous leukemia), 5 patients with multiple myeloma following autologous stem cell transplantation, 1 patient with multiple myeloma perimobilization, 2 patients with NHL post chemotherapy, and 1 patient with CLL. All 13 patients required hospitalization. Six (43%) were admitted to the intensive care unit (ICU), of whom 4 (67%) died. We evaluated B cell and T cell responses to H1N1 infection prospectively in these patients compared with those in 4 otherwise healthy controls. Within 12 weeks of diagnosis, only 6 of 11 patients developed seropositive antibody titers as measured by hemagglutination-inhibition or microneutralization assays, compared with 4 of 4 controls. H1N1-specific T cells were detected in only 2 of 8 evaluable patients compared with 4 of 4 controls. H1N1-specific T cells were functional, capable of producing interferon γ, tumor necrosis factor α, and CD107a mobilization. Furthermore, CD154 was up-regulated on CD4(+) T cells in 3 of 4 controls and 2 of 2 patients who had both B cell and T cell responses to H1N1. Post-H1N1 infection, 5 of 8 patients developed seasonal influenza-specific T cells, suggesting cross-reactivity induced by H1N1 infection. These data offer novel insights into humoral and cell-mediated immunologic responses to primary H1N1 infection.
Asunto(s)
Neoplasias Hematológicas/inmunología , Inmunidad Celular , Inmunidad Humoral , Gripe Humana/inmunología , Adulto , Anciano , Anticuerpos/análisis , Anticuerpos/inmunología , Ligando de CD40/análisis , Estudios de Casos y Controles , Femenino , Pruebas de Inhibición de Hemaglutinación , Neoplasias Hematológicas/patología , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/prevención & control , Interferón gamma/análisis , Interferón gamma/biosíntesis , Proteína 1 de la Membrana Asociada a los Lisosomas/análisis , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante de Células Madre , Trasplante HomólogoRESUMEN
Natural killer (NK) cells exert antimyeloma cytotoxicity. The balance between inhibition and activation of NK-cells played by the inherited repertoire of killer immunoglobulin-like receptor (KIR) genes therefore may influence prognosis. One hundred eighty-two patients with multiple myeloma (MM) were analyzed for KIR repertoire. Multivariate analysis showed that progression-free survival (PFS) after autologous stem cell transplantation (ASCT) was significantly shorter for patients who are KIR3DS1(+) (P = .01). This was most evident for patients in complete or partial remission (good risk; GR) at ASCT. The relative risk (RR) of progression or death for patients with KIR3DS1(+) compared with KIR3DS1(-) was 1.9 (95% CI, 1.3-3.1; P = .002). The most significant difference in PFS was observed in patients with GR KIR3DS1(+) in whom HLA-Bw4, the ligand for the corresponding inhibitory receptor KIR3DL1, was missing. Patients with KIR3DS1(+) KIR3DL1(+) HLA-Bw4(-) had a significantly shorter PFS than patients who were KIR3DS1(-), translating to a difference in median PFS of 12 months (12.2 vs 24 months; P = .002). Our data show that KIR-human leukocyte antigen immunogenetics represent a novel prognostic tool for patients with myeloma, shown here in the context of ASCT, and that KIR3DS1 positivity may identify patients at greater risk of progression.