IntroductionA major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.MethodsBlood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry.ResultsLymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).ConclusionsIn vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

Progressive multifocal leukoencephalopathy (PML) is a rare but debilitating and frequently fatal viral disease of the central nervous system, primarily affecting individuals with chronically and severely suppressed immune systems. The disease was relatively obscure until the outbreak of HIV/AIDS, when it presented as one of the more frequent opportunistic infections in this immune deficiency syndrome. It attracted additional attention from the medical and scientific community following the discovery of significant PML risk associated with natalizumab, a monoclonal antibody used for treatment of relapsing-remitting multiple sclerosis. This was followed by association of PML with other immunosuppressive or immunomodulating drugs. PML is currently untreatable disease with poor outcomes, so it is a significant concern when developing new immunotherapies. Current prophylaxis and treatment of PML are focused on immune reconstitution, restoration of immune responses to JC virus infection, and eventual suppression of immune reconstitution inflammatory syndrome. This approach was successful in reducing the incidence of PML and improved survival of PML patients with HIV infection. However, the outcome for the majority of PML patients, regardless of their medical history, is still relatively poor. There is a high unmet need for both prophylaxis and treatment of PML. The aim of this review is to discuss potential drug candidates for prophylaxis and treatment of PML with a critical review of previously conducted and completed PML treatment studies as well as to provide perspectives for future therapies.

Functional interleuin-8 (IL-8) receptors (IL-8RA and IL-8RB:CXCR1 and CXCR2, respectively) have been described in human, monkey, dog, rabbit, and guinea pig. Although three IL-8R homologues have been found in rat, only one of these, rat CXCR2, appears to be functional based on responsiveness to ligands. Similarly, CXC chemokines induce biological responses through the murine homolog of CXCR2, but the identification of functional rodent CXCR1 homologues has remained elusive. We have identified and characterized the mouse CXCR1 homologue (mCXCR1). Murine CXCR1 shares 68 and 88% amino acid identity with its human and rat counterparts, respectively. Similar to the tissue distribution pattern of rat CXCR1, we found murine CXCR1 mRNA expression predominantly in lung, stomach, bone marrow, and leukocyte-rich tissues. In contrast to previous reports, we determined that mCXCR1 is a functional receptor. We show predominant engagement of this receptor by mouse GCP-2/CXCL6, human GCP-2, and IL-8/CXCL8 by binding, stimulation of GTP␥S exchange, and chemotaxis of mCXCR1-transfected cells. Furthermore, murine CXCR1 is not responsive to the human CXCR2 ligands ENA-78/CXCL5, NAP-2/CXCL7, GRO-␣, -␤, -␥/CXCL1-3, or rat CINC-1-3. In addition, we show concomitant elevation of mCXCR1 and its proposed major ligand, GCP-2, positively correlated with paw swelling in murine collagen-induced arthritis. This report represents the first description of a functional CXCR1-like receptor in rodents.

Sepsis is a heterogeneous syndrome comprising a highly diverse and dynamic mixture of hyperinflammatory and compensatory anti-inflammatory immune responses. This immune phenotypic diversity highlights the importance of proper patient selection for treatment with the immunomodulatory drugs that are entering clinical trials. To better understand the serial changes in immunity of critically ill patients and to evaluate the potential efficacy of blocking key inhibitory pathways in sepsis, we undertook a broad phenotypic and functional analysis of innate and acquired immunity in the same aliquot of blood from septic, critically ill nonseptic, and healthy donors. We also tested the ability of blocking the checkpoint inhibitors programmed death receptor-1 (PD-1) and its ligand (PD-L1) to restore the function of innate and acquired immune cells. Neutrophil and monocyte function (phagocytosis, CD163, cytokine expression) were progressively diminished as sepsis persisted. An increasing frequency in PD-L1-suppressor phenotype neutrophils [low-density neutrophils (LDNs)] was also noted. PD-L1 LDNs and defective neutrophil function correlated with disease severity, consistent with the potential importance of suppressive neutrophil populations in sepsis. Reduced neutrophil and monocyte function correlated both with their own PD-L1 expression and with PD-1 expression on CD8 T cells and NK cells. Conversely, reduced CD8 T cell and NK cell functions (IFN-γ production, granzyme B, and CD107a expression) correlated with elevated PD-L1 LDNs. Importantly, addition of antibodies against PD-1 or PD-L1 restored function in neutrophil, monocyte, T cells, and NK cells, underlining the impact of the PD-1:PD-L1 axis in sepsis-immune suppression and the ability to treat multiple deficits with a single immunomodulatory agent.

IntroductionEpstein-Barr virus (EBV) is a member of the human herpesvirus family that infects over 95% of the United States population. 1 Most infections occur in childhood and are asymptomatic; infection of adolescents and young adults with EBV often results in infectious mononucleosis. EBV is associated with a spectrum of lymphoproliferative diseases in patients with congenital or acquired immunodeficiency.Chronic active EBV infection (CAEBV) is a rare and often fatal disorder that occurs in previously healthy persons and seemingly immunocompetent persons. 2 The disease has been defined by the presence of 3 features. 3,4 First, patients have a severe progressive illness that began as a primary EBV infection, or is associated with abnormal EBV-specific antibody titers that include markedly elevated antibodies to viral capsid antigen (VCA) and early antigens (EAs). Second, histology shows evidence of major organ involvement such as lymphadenitis, hemophagocytosis, meningoencephalitis, or persistent hepatitis. Third, elevated EBV DNA, RNA, or proteins are demonstrable by in situ hybridization or immunohistochemical staining of affected tissues. Recent studies showed that patients with CAEBV can also have markedly elevated levels of EBV DNA in the peripheral blood and this criterion has been used diagnostically in some cases. 5 Patients with CAEBV often develop a progressive cellular and humoral immunodeficiency with pancytopenia and hypogammaglobulinemia that renders them susceptible to opportunistic infections or B-or T-cell lymphoproliferative disease. 3 Therapy for CAEBV is unsatisfactory and, at best, progression of disease is temporarily delayed.The etiology of CAEBV is unknown. Two studies suggested that persons with CAEBV were infected with unusual lytic strains of virus. 6,7 However, the finding of the same lytic strain of EBV in the unaffected father of one of the patients, and in healthy controls, 8 suggests that other factors, including inherited abnormalities in the response to EBV, contribute to the pathogenesis of the disease. Four observations favor a genetic cause for CAEBV. First, CAEBV is rare in the United States, but relatively common in Japan, Korea, and China. Most patients reported to have fulminant EBV-positive T-cell lymphoproliferative disease following acute and/or chronic EBV infection have been Asian in origin. 9 Second, specific mutations in the signaling lymphocyte activation molecule (SLAM) associated protein (SAP) gene have been identified in boys with a disease that shares many of the features of CAEBV, the X-linked lymphoproliferative disease (XLPD). [10][11][12] Third, 2 studies showed that cytotoxic T lymphocyte (CTL) or natural killer (NK) cell activity was reduced in patients with CAEBV and in their parents. 13,14 Fourth, gene mutations and polymorphisms have been associated with severe infections with herpesviruses including EBV. [15][16][17] Taken together, these findings suggest that a genetic abnormality could underlie some cases of CAEBV.Here we describe a patient with ...