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Regulatory B cells (Bregs) ameliorate autoimmune disease and prevent allograft rejection. Conversely, they hinder effective clearance of pathogens and malignancies. Breg activity is mainly attributed to IL-10 expression, but also utilizes additional regulatory mechanisms such as TGF-β, FasL, IL-35, and TIGIT. Although Bregs are present in various subsets defined by phenotypic markers (including canonical B cell subsets), our understanding of Bregs has been limited by the lack of a broadly inclusive and specific phenotypic or transcriptional marker. TIM-1, a broad marker for Bregs first identified in transplant models, plays a major role in Breg maintenance and induction. Here, we expand on the role of TIM-1+ Bregs in immune tolerance and propose TIM-1 as a unifying marker for Bregs that utilize various inhibitory mechanisms in addition to IL-10. Further, this review provides an in-depth assessment of our understanding of Bregs in transplantation as elucidated in murine models and clinical studies. These studies highlight the major contribution of Bregs in preventing allograft rejection, and their ability to serve as highly predictive biomarkers for clinical transplant outcomes.

T cells are central to graft rejection, and therefore preventing T cells from recognizing and destroying allografts remains an important area of transplant research. However, T cells are also required for transplant tolerance; a subset can enforce a state of tolerance by functioning as regulatory cells. As both rejection and regulation directed against alloantigens require T-cell activation, costimulatory molecules undoubtedly play an important role in regulating both processes and ultimately the fate of the allograft. However, costimulation involves an incredibly complex array of interactions that may act contemporaneously or at different times; these interactions can have additive or opposing effects on T-cell activation or differentiation. While some costimulatory molecules mediate activation of naive T cells or generation of memory T cells, others inhibit T-cell activation and promote anergy or apoptosis. Moreover, a given pathway can have diametrically different effects on T-effector cells and regulatory T cells (Tregs). Such a complexity presents both challenges and opportunities in targeting T-cell costimulatory pathways to promote transplant tolerance. In this review article, we provide a summary of recent advances in our understanding of T-cell costimulatory pathways in regulating different phases of the T-cell response in transplant models. We focus specifically on costimulatory molecules in the immunoglobulin (Ig) superfamily, tumor necrosis factor (TNF)/TNF receptor superfamily, and in the emerging T-cell Ig domain and mucin domain family (TIM), highlighting their unique and redundant roles in regulating the T-effector and Treg responses after transplantation. Finally, we summarize emerging approaches toward inducing tolerance by tipping the balance between cytopathic T-effector cells and protective Tregs by selectively targeting specific T-cell costimulatory pathways that are critically involved.

Rifalazil is a benzoxazinorifamycin which inhibits bacterial DNA-dependent RNA polymerase. The benzoxazine ring endows benzoxazinorifamycins with unique physical and chemical characteristics which favor the use of rifalazil and derivatives in treating diseases caused by the obligate intracellular pathogens of the genus chlamydia. Minimal inhibitory concentrations of benzoxazinorifamycins against chlamydia are in the pg/mL range. These compounds have potential as monotherapeutic agents to treat chlamydia-associated disease because they retain activity against chlamydia strains resistant to currently approved rifamycins such as rifampin. A pivotal clinical trial with rifalazil has been initiated for the treatment of peripheral arterial disease. The rationale for this innovative use of rifalazil, including the association of C. pneumoniae in atherosclerotic plaque formation, as well as rifalazil's potency and efficacy against chlamydia in both preclinical and clinical studies, is discussed. Other benzoxazino derivatives may have utility as stand-alone topical antibacterials or combination antibacterials to treat serious Gram-positive infections. None of the benzoxazinorifamycins examined to date induce the cytochrome P450 3A4 enzyme. This is in contrast to currently approved rifamycins which are strong inducers of P450 enzymes, resulting in drug-drug interactions that limit the clinical utility of this drug class.

The destiny of activated T cells is critical to the ultimate fate of immune response. After encountering antigen, naïve T cells receive signal 1 through the T-cell receptor (TCR)-major histocompatibility complex (MHC) plus antigenic peptide complex and signal 2 through "positive" costimulatory molecules leading to full activation. "Negative" T-cell costimulatory pathways, on the other hand, function to downregulate immune responses. The purpose of this article is to review the current state of knowledge and recent advances in our understanding of the functions of the positive and negative T-cell costimulatory pathways in alloimmune responses. Specifically, we discuss the functions of the CD28:B7 and the tumor necrosis factor receptor (TNFR):tumor necrosis factor (TNF) family of molecules in allograft rejection and tolerance. We address the following important questions: are T-cell costimulatory pathways merely redundant or do they provide distinct and unique functions? What are the important and unique interactions between the various pathways? And, what are the effects and mechanisms of targeting of these pathways in different types and patterns of allograft rejection and tolerance models?

Metal ions were evaluated as potential antimicrobial agents suitable for local delivery in the oral cavity for the treatment of periodontitis. Silver nitrate, copper chloride, and zinc chloride were tested for antimicrobial activity in in vitro killing assays conducted in phosphate buffered saline with a series of oral bacteria including gram-negative periodontal pathogens and gram-positive streptococci. Copper and zinc salts failed to exhibit strong and consistent activity against periodontal pathogens. In contrast, silver at a concentration of 0.5 microg/mL produced a 3 log10 reduction in colony forming units (CFU)/mL or greater against all periodontal pathogens tested including Porphyromonas gingivalis, Prevotella intermedia, Prevotella denticola, Bacteroides forsythus, Fusobacterium nucleatum vincentii, Campylobacter gracilis, Campylobacter rectus, Eikenella corrodens, and Actinobacillus actinomycetemcomitans. In comparison, substantially higher concentrations of silver nitrate failed to kill oral streptococci. A silver nitrate concentration of 25 microg/mL produced log10 reductions in CFU/mL of 3.5-5 in killing assays performed in human serum against P. gingivalis, demonstrating the ability of silver to retain activity in a biological medium similar to that encountered in vivo in the periodontal pocket. These results identify silver nitrate, an antimicrobial that may possess advantages over traditional antibiotics, as a potential agent for controlled release local delivery in the oral cavity for the treatment of periodontitis.

Rifalazil is a benzoxazinorifamycin which inhibits bacterial DNA-dependent RNA polymerase. The benzoxazine ring endows benzoxazinorifamycins with unique physical and chemical characteristics which favor the use of rifalazil and derivatives in treating diseases caused by the obligate intracellular pathogens of the genus chlamydia. Minimal inhibitory concentrations of benzoxazinorifamycins against chlamydia are in the pg/mL range. These compounds have potential as monotherapeutic agents to treat chlamydia-associated disease because they retain activity against chlamydia strains resistant to currently approved rifamycins such as rifampin. A pivotal clinical trial with rifalazil has been initiated for the treatment of peripheral arterial disease. The rationale for this innovative use of rifalazil, including the association of C. pneumoniae in atherosclerotic plaque formation, as well as rifalazil's potency and efficacy against chlamydia in both preclinical and clinical studies, is discussed. Other benzoxazino derivatives may have utility as stand-alone topical antibacterials or combination antibacterials to treat serious Gram-positive infections. None of the benzoxazinorifamycins examined to date induce the cytochrome P450 3A4 enzyme. This is in contrast to currently approved rifamycins which are strong inducers of P450 enzymes, resulting in drug-drug interactions that limit the clinical utility of this drug class.