Surveillance of γδ T Cells Predicts Cytomegalovirus Infection Resolution in Kidney Transplants

Cytomegalovirus (CMV) infection in solid-organ transplantation is associated with increased morbidity and mortality, particularly if a CMV mutant strain with antiviral resistance emerges. Monitoring CMV–specific T cell response could provide relevant information for patient care. We and others have shown the involvement of Vδ2^neg γδ T cells in controlling CMV infection. Here, we assessed if Vδ2^neg γδ T cell kinetics in peripheral blood predict CMV infection resolution and emergence of a mutant strain in high–risk recipients of kidney transplants, including 168 seronegative recipients receiving organs from seropositive donors (D+R−) and 104 seropositive recipients receiving antithymocyte globulins (R+/ATG). Vδ2^neg γδ T cell percentages were serially determined in patients grafted between 2003 and 2011. The growing phase of Vδ2^neg γδ T cells was monitored in each infected patient, and the expansion rate during this phase was estimated individually by a linear mixed model. A Vδ2^neg γδ T cell expansion rate of ˃0.06% per day predicted the growing phase. The time after infection at which an expansion rate of 0.06% per day occurred was correlated with the resolution of CMV DNAemia (r=0.91; P<0.001). At 49 days of antiviral treatment, Vδ2^neg γδ T cell expansion onset was associated with recovery, whereas absence of expansion was associated with recurrent disease and DNAemia. The appearance of antiviral–resistant mutant CMV strains was associated with delayed Vδ2^neg γδ T cell expansion (P<0.001). In conclusion, longitudinal surveillance of Vδ2^neg γδ T cells in recipients of kidney transplants may predict CMV infection resolution and antiviral drug resistance.     

Regulatory T cells: the future of autoimmune disease treatment

ABSTRACT

Introduction: CD4 + T regulatory cells (Tregs) have been described as the most potent immunosuppressive cells in the human body. They have been found to control autoimmunity, and clinical attempts have been made to apply them to treat autoimmune diseases. Some specific pathways utilized by Tregs in the regulation of immune response or Tregs directly as cellular products are tested in the clinic.

Areas covered: Here, we present recent advances in the research on the biology and clinical applications of Tregs in the treatment of autoimmune diseases.

Expert opinion: Regulatory T cells seem to be a promising tool for the treatment of autoimmune diseases. The development of both cell-based therapies and modern pharmacotherapies which affect Tregs may strongly improve the treatment of autoimmune disorders. Growing knowledge about Treg biology together with the latest biotechnology tools may give an opportunity for personalized therapies in these conditions.     

The role of antigen-specific and non-specific immunotherapy in the treatment of cancer

Immunotherapy in the treatment of cancer is increasing, particularly with the recent FDA approval of sipuleucel-T and ipilimumab. The efficacy of anti-tumor immunotherapies has been modest compared to their theoretical and pre-clinical promise. This review evaluates the promise and pitfalls of immunotherapy and highlight some of the obstacles to improving anti-tumor immunotherapy: the need for technical refinement of therapies, the need for an increased understanding of how best to combine therapies with traditional cytotoxic therapies, the inability of patients to mount an effective immune response either due to disease burden or tumor induced immune suppression, the significant toxicities associated with many immunotherapies, and the lack of strongly immunogenic antigens required by many therapies. Further, antigen-non-specific immunotherapies, including cytokines such as interleukins and interferons, immuno-stimulatory agents such as CpG oligonucleotides, or BCG, antibodies targeted against receptors such as the agonistic CD40 or inhibitory CTLA-4 antibodies, and enzyme inhibitors such as those targeting cyclo-oxygenase or indolamine-2,3-dioxygenase are discussed. In addition, potential mechanisms of these therapies such as direct anti-tumor effects, reversal of immune suppression, activation of innate immunity, and antigen-non-specific T-cell activation are reviewed. We also appraise the potential of these antigen-non-specific therapies to overcome some of the previously described pitfalls of immunotherapy. Lastly, we discuss a recent series of studies from our laboratory demonstrating the importance of antigen-non-specific ‘bystander activation’ of memory T-lymphocytes by immunomodulatory therapies such as interleukin-2 and the antigen-non-specific anti-tumor effects of these cells.     

Unravelling the complexity of cancer–immune system interplay

The immune system has an intricate and complex relationship with tumorigenesis; while it has the capacity to identify and eliminate cancerous cells, the emergence of a tumor signifies its failure to do this. Thus, the immune–tumor interplay is paradoxical as through initial suppression of tumor growth, an immunologically silent or even suppressive tumor evolves. Furthermore, certain immune processes, such as chronic inflammation and immunosuppression, can facilitate malignant progression. Nevertheless, immunotherapeutic approaches can manipulate the immune milieu to improve the therapeutic outcomes of cancer treatments. Furthermore, particular conventional cancer therapies also have immunostimulatory properties in their own right. An in-depth understanding of the intimate involvement of the immune system in tumorigenesis and the potential to manipulate this interaction to improve disease outcomes will enable the development of new and broadly effective cancer therapies.     

Baby born too soon: an overview and the impact beyond the infection

Spontaneous preterm delivery, prematurity, and low birth weight due to prematurity account for a great part of neonatal morbidity and mortality. Inflammation may cause preterm labor, with the involvement of different mediators that produce diverse aspects of the inflammatory response. Although bacteria are considered to be the main trigger for intrauterine infection/inflammation, immunological factors also appear to be involved. Recently, molecular genetic studies have helped us better understand the underlying pathophysiologic processes. During mammalian pregnancy, maternal–fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. This review focuses on the specific immune parameters that become altered during human pregnancy, the identity and function of some immune modulators that have been best characterized to date, as well as a comprehensive evaluation of the pregnancy-associated mechanisms that downregulate proinflammatory immunity to a level sufficient to prevent the triggering of premature common pathway of labor and damage to developing organs.     

Increased circulating apoptotic lymphocytes in children with Down syndrome

Down syndrome (DS) resembles immunodeficiency with increased infections, auto‐immune diseases, and hematological malignancies. Until now, immunological studies in DS mainly focused on T‐lymphocytes. We recently described a profound B‐lymphocytopenia in children with DS. This could be caused by increased apoptosis. Therefore, we determined expression of flowcytometric markers for apoptosis [Annexin‐V (AV) and propidium iodide (PI)] on peripheral lymphocytes in 72 children with DS and 32 age‐matched controls (AMC). Within the total lymphocyte compartment, apoptosis was more pronounced in DS; it increased with age. Moreover, apoptosis was highest within the B‐lymphocyte compartment which may be a contributing factor to the B‐lymphocytopenia found in DS. Pediatr Blood Cancer 2012; 59: 1310–1312. © 2012 Wiley Periodicals, Inc.