Perinatal Exposure to Δ⁹-Tetrahydrocannabinol Triggers Profound Defects in T Cell Differentiation and Function in Fetal and Postnatal Stages of Life, Including Decreased Responsiveness to HIV Antigens

Abstract

Marijuana abuse is very prominent among pregnant women. Although marijuana cannabinoids have been shown to exert immunosuppression in adults, virtually nothing is known about the effects of marijuana use during pregnancy on the developing immune system of the fetus and during postnatal life. We noted that murine fetal thymus expressed high levels of the cannabinoid receptors CB1 and CB2. Moreover, perinatal exposure to ⌬ 9 -tetrahydrocannabinol (THC) had a profound effect on the fetus as evidenced by a decrease in thymic cellularity on gestational days 16, 17, and 18 and postgestational day 1 and marked alterations in T cell subpopulations. These outcomes were reversed by CB1/CB2 antagonists, suggesting that THCmediated these effects through cannabinoid receptors. Thymic atrophy induced in the fetus correlated with caspase-dependent apoptosis in thymocytes. Thymic atrophy was the result of direct action of THC and not based on maternal factors inasmuch as THC was able to induce T cell apoptosis in vitro in fetal thymic organ cultures. It is noteworthy that perinatal exposure to THC also had a profound effect on the immune response during postnatal life. Peripheral T cells from such mice showed decreased proliferative response to T cell mitogen as well as both T cell and antibody response to HIV-1 p17/p24/gp120 antigens. Together, our data demonstrate for the first time that perinatal exposure to THC triggers profound T cell dysfunction, thereby suggesting that the offspring of marijuana abusers who have been exposed to THC in utero may be at a higher risk of exhibiting immune dysfunction and contracting infectious diseases including HIV.

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

“…This observation argues against transdifferentiation as a mechanism eliciting altered islet architecture in MAGL −/− mice. Because eCBs modulate cell migration and survival in the nervous system, adipose tissue, muscle, and immune system (13,22,(28)(29)(30)(31)(32), we instead favor that altered cell migration could, at least in part, contribute to incomplete cell segregation in MAGL −/− mice (Fig. S3).…”

“…Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10)(11)(12)(13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15).…”

Immunoregulatory Role of Cannabinoids during Infectious Disease

“…Treatment with the cannabinoid decreased early mortality, however [72,74]. Interestingly, this effect is gender-dependent, as female macaques in the same condition showed that THC treatment did not protect them from early mortality [75].…”

“…Both effects are mediated by the activation of CB1 and CB2. Immune function, tested with the HIV-1 p17/p24/gp120 protein in adult mice exposed prenatally to THC, revealed that these animals exhibited a lower T cell proliferation rate as well as lower amounts of specific antibodies against HIV-1 p17/p24/gp120, suggesting that prenatal cannabis exposure can lead to a less efficient immune system in adulthood, increasing the risk of infectious diseases [72].…”

Exposure of Adolescent Mice to Delta-9-Tetrahydrocannabinol Induces Long-Lasting Modulation of Pro- and Anti-Inflammatory Cytokines in Hypothalamus and Hippocampus Similar to that Observed for Peripheral Macrophages

“…During this period, mice received increasing s.c. doses of THC once a day (5 mg/kg pnd 80-82; 10 mg/kg pnd 83-85; 15 mg/kg pnd 86-89) or its vehicle. The dose protocol was chosen on the basis of previous experiments from our and other groups, and the dosage was increased over 10 days to counteract the possible development of tolerance, which has been previously observed for some immune responses (Massi et al 1998;Lombard et al 2011;Moretti et al 2014). Moreover, we have previously demonstrated that this dosage reached plasma concentrations in mice similar to those measured in human heavy marijuana smokers (Moretti et al 2014).…”