Immunocompromised host section: Adoptive T-cell therapy for dsDNA viruses in allogeneic hematopoietic cell transplant recipients.

Purpose Of Review: Double-stranded DNA (dsDNA) viruses remain important causes of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). As treatment options are limited, adoptive therapy with virus-specific T cells (VST) is promising in restoring immunity and thereby preventing and treating virus infections. Here we review current evidence and recent advances in the field of VST for dsDNA viruses in allogeneic HCT recipients.

Interferon-λ Enhances the Differentiation of Naive B Cells into Plasmablasts via the mTORC1 Pathway.

Type III interferon (interferon lambda [IFN-λ]) is known to be a potential immune modulator, but the mechanisms behind its immune-modulatory functions and its impact on plasmablast differentiation in humans remain unknown. Human B cells and their subtypes directly respond to IFN-λ. Using B cell transcriptome profiling, we investigate the immune-modulatory role of IFN-λ in B cells.

T-Cell-Mediated Cross-Protective Immunity.

Human invasive fungal infections are caused by different mold and yeast species. Hence, cross-reactive T cells that recognize conserved epitopes of various fungal pathogens are of special interest for vaccination protocols or adoptive T cell transfer. Here, we describe an ELISpot-based method to test cross-reactivity of T cell lines or clones to different molds and yeasts.

Host response to fungal infections - how immunology and host genetics could help to identify and treat patients at risk.

In spite of the ever-increasing incidence and poor outcome of invasive fungal infections in immune compromised patients, there is currently no reliable method to accurately predict the risk, to monitor the outcome and to treat these infections. Protective immunity against Candida and Aspergillus depends on a highly coordinated interaction between the innate and adaptive immune systems. Genetic and immunological defects in components of these networks result in increased risk of invasive fungal infections among patients undergoing chemotherapy or transplant recipients.

Immune recovery in HIV-infected patients after Candida esophagitis is impaired despite long-term antiretroviral therapy.

Objective: Candida esophagitis belongs to the most common AIDS-defining diseases; however, a comprehensive immune pathogenic concept is lacking.

Design: We investigated the immune status of 37 HIV-1-infected patients from the Swiss HIV cohort study at diagnosis of Candida esophagitis, 1 year before, 1 year later and after 2 years of suppressed HIV RNA. We compared these patients with three groups: 37 HIV-1-infected patients without Candida esophagitis but similar CD4 cell counts as the patients at diagnosis (advanced HIV group), 15 HIV-1-infected patients with CD4 cell counts higher than 500 cells/μl, CD4 cell nadirs higher than 350 cells/μl and suppressed HIV RNA under combination antiretroviral therapy (cART) (early cART group) and 20 healthy individuals.

Combination therapy for multidrug-resistant cytomegalovirus disease.

Multidrug-resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV-seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV-seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re-transplantation from a CMV-seropositive donor supported by adoptive transfer of pp65-specific T cells and maribavir was followed by lasting suppression.

T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells.

Background Aims: Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) belong to the most dreaded complications of immunosuppression. The efficacy of EBV-specific T-cell transfer for PTLD has been previously shown, yet the optimal choice of EBV-derived antigens inducing polyclonal CD4(+) and CD8(+) T cells that cover a wide range of human leukocyte antigen types and efficiently control PTLD remains unclear.

Methods: A pool of 125 T-cell epitopes from seven latent and nine lytic EBV-derived proteins (EBVmix) and peptide pools of EBNA1, EBNA3c, LMP2a and BZLF1 were used to determine T-cell frequencies and to isolate T cells through the use of the interferon (IFN)-γ cytokine capture system.

Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs.

Acute graft-versus-host disease is still a major cause of transplant-related mortality after allogeneic stem cell transplantation. It requires immunosuppressive treatments that broadly abrogate T cell responses, including beneficial ones directed against tumor cells or infective pathogens. Inhibition of the heat shock protein of 90 kDa has been demonstrated to eliminate tumor cells, as well as alloreactive T cells while preserving antiviral T cell immunity.

Immune Reconstitution After Allogeneic Hematopoietic Stem Cell Transplantation and Association With Occurrence and Outcome of Invasive Aspergillosis.

Background: Invasive aspergillosis (IA) remains a leading cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To date, no reliable immunological biomarkers for management and outcome of IA exist. Here, we investigated reconstitution of antifungal immunity in patients during the first 12 months after HSCT and correlated it with IA.

Multispecific Aspergillus T cells selected by CD137 or CD154 induce protective immune responses against the most relevant mold infections.

Background: Aspergillus and Mucorales species cause severe infections in patients after hematopoietic stem cell transplantation (HSCT). Induction of antifungal CD4(+) T-helper type 1 (Th1) immunity is an appealing strategy to combat these infections. Immunotherapeutic approaches are so far limited because of a lack of antigens inducing protective T cells, their elaborate production, and the need of targeting a broad spectrum of pathogenic fungi.

Generation of a multipathogen-specific T-cell product for adoptive immunotherapy based on activation-dependent expression of CD154.

Viral and fungal infections remain a leading cause of mortality in patients after hematopoietic stem cell transplantation (HSCT). Adoptive transfer of multipathogen-specific T cells is promising in restoring immunity and thereby preventing and treating infections, but approaches are currently limited because of time-consuming and laborious procedures. Therefore, we investigated a new strategy to simultaneously select T cells specific for viral and fungal pathogens based on activation-dependent expression of CD154.

Cross-protective TH1 immunity against Aspergillus fumigatus and Candida albicans.

T cell-mediated heterologous immunity to different pathogens is promising for the development of immunotherapeutic strategies. Aspergillus fumigatus and Candida albicans, the 2 most common fungal pathogens causing severe infections in immunocompromised patients, are controlled by CD4+ type 1 helper T (T(H)1) cells in humans and mice, making induction of fungus-specific CD4+ T(H)1 immunity an appealing strategy for antifungal therapy. We identified an immunogenic epitope of the A fumigatus cell wall glucanase Crf1 that can be presented by 3 common major histocompatibility complex class II alleles and that induces memory CD4+ T(H)1 cells with a diverse T-cell receptor repertoire that is cross-reactive to C albicans.

Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Current treatment of GVHD relies on immunosuppressive regimens, considerably increasing the incidence of opportunistic infections. As T cells mediate both GVHD as well as protection against viral infections and the malignant disease, strategies to selectively target host-reactive T cells without impairing pathogen- and disease-specific immunity are highly warranted.