Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-g and TNF-a. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

Dendritic cells (DCs) encompass a heterogeneous population of cells capable of orchestrating innate and adaptive immune responses. The ability of DCs to act as professional antigen presenting cells has been the foundation for the development and utilization of these cells as vaccines in cancer immunotherapy. DCs are also endowed with the non-conventional property of directly killing tumor cells. The current study investigates the regulation of murine DC cytotoxic function by T lymphocytes. We provide evidence that CD4+ Th-1, but not Th-2, Th-17 cells or Treg are capable of inducing DC cytotoxic function. IFN-γ was identified as the major factor responsible for Th-1-induced DC tumoricidal activity. Tumor cell killing mediated by Th-1-activated killer DCs (Th-1 KDCs) was dependent on inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. Importantly, Th-1 KDCs were capable of presenting the acquired antigens from the killed tumor cells to T lymphocytes in vitro or in vivo. These observations open new possibilities for the application of KDCs in cancer immunotherapy.

IntroductionThe primary objective of cancer immunotherapy is to promote tumor elimination through the activation of innate and adaptive immune responses. Successful immunotherapy relies on vaccination strategies endowed with the dual capability of inducing tumor-specific lymphocytes while overcoming the mechanisms of immune tolerance. CD4 ϩ CD25 ϩ FoxP3 ϩ regulatory T lymphocytes (Tregs) critically contribute to the occurrence and persistence of tumor-induced tolerance. 1 An increase in the frequency of these immunosuppressive cells in cancer patients has been widely reported. Treg expansion observed during tumor progression may result from the proliferation of naturally occurring Tregs (nTregs) or from the conversion of CD4 ϩ CD25 Ϫ FoxP3 Ϫ T cells into CD4 ϩ CD25 ϩ FoxP3 ϩ Tregs (iTregs). 2,3 Tregs dampen immune responses by suppressing the function of the effectors CD4 ϩ , CD8 ϩ , and natural killer (NK) cells [4][5][6][7] and by inhibiting dendritic cell activation. [8][9][10] Because Tregs are one of the main barriers for the eradication of tumors by immune cells, their therapeutic depletion or their functional inactivation using drugs or antibodies improves responses to cancer immunotherapy, such as dendritic cell-based vaccines. [11][12][13][14][15][16] However, the selective elimination or inactivation of Tregs constitutes a major challenge because these cells share the same surface markers as activated conventional, nonsuppressive T cells. Indeed, antibody-based approaches indistinguishably target both Tregs and activated effector T lymphocytes. Likewise, chemotherapeutic agents such as cyclophosphamide, which are used to eliminate Tregs, do not target these cells selectively.Several reports have indicated that the adoptive transfer of allogeneic T cells may increase the efficacy of tumor immunotherapy by providing adjuvant/"danger" signals to the host immune cells. 17,18 A method has been optimized allowing for the efficient generation in vitro of a large number of allogeneic CD3/CD28 cross-linked T helper-1 (Th-1) memory T cells. 19 Adoptive transfer of these Th-1 lymphocytes stimulates anticancer immunity and significantly improves the survival of mice lethally injected with BCL1 leukemia cells. 19,20 This effect partly stems from cytokine production by activated T lymphocytes, which foster the establishment of protective type-1 immune responses. 18 However, the effects of type I cytokines, including interferon-␥ (IFN-␥), on Tregs have been discrepant in previous studies. As an essential effector cytokine for cell-mediated immunity, exogenous or autocrine IFN-␥ has been reported to negatively regulate Treg generation. 21,22 Other studies have found that IFN-␥ enhances activation-induced cell death and that it thereby may regulate the expansion and persistence of effector T cells by promoting apoptosis. 23,24 In the present study, we report that effector-memory CD4 ϩ Th-1 (emTh-1) cells are capable not only of fostering the establishment of type-1 immune responses, but also of critically impairing t...

Background: We present the rationale for a novel allo-priming approach to serve the elderly as a universal anti-virus vaccine, as well serving to remodel the aging immune system in order to reverse immunosenescence and inflammaging. This approach has the potential to protect the most vulnerable from disease and provide society an incalculable economic benefit. Allo-priming healthy elderly adults is proposed to provide universal protection from progression of any type of viral infection, including protection against progression of the current outbreak of COVID-19 infection, and any future variants of the causative SARS-CoV-2 virus or the next 'Disease X' . Allo-priming is an alternative approach for the COVID-19 pandemic that provides a back-up in case vaccination strategies to elicit neutralizing antibody protection fails or fails to protect the vulnerable elderly population. The allo-priming is performed using activated, intentionally mismatched, ex vivo differentiated and expanded living Th1-like cells (AlloStim ® ) derived from healthy donors currently in clinical use as an experimental cancer vaccine. Multiple intradermal injections of AlloStim ® creates a dominate titer of allo-specific Th1/CTL memory cells in circulation, replacing the dominance of exhausted memory cells of the aged immune system. Upon viral encounter, by-stander activation of the allo-specific memory cells causes an immediate release of IFN-ϒ, leading to development of an "anti-viral state", by-stander activation of innate cellular effector cells and activation of cross-reactive allo-specific CTL. In this manner, the non-specific activation of allospecific Th1/CTL initiates a cascade of spatial and temporal immune events which act to limit the early viral titer. The release of endogenous heat shock proteins (HSP) and DAMP from lysed viral-infected cells, in the context of IFN-ϒ, creates of conditions for in situ vaccination leading to viral-specific Th1/CTL immunity. These viral-specific Th1/CTL provide sterilizing immunity and memory for protection from disease recurrence, while increasing the pool of Th1/ CTL in circulation capable of responding to the next viral encounter. Conclusion:Allo-priming has potential to provide universal protection from viral disease and is a strategy to reverse immunosenescence and counter-regulate chronic inflammation (inflammaging). Allo-priming can be used as an adjuvant for anti-viral vaccines and as a counter-measure for unknown biological threats and bio-economic terrorism.