Usually, MPTP treatment causes an increase in the number of nigral microglia, which may be due to resident microglia replication, or the influx of bone-marrow-derived cells from the periphery. The increased number of activated microglia in the SNc is thought to contribute to MPTP-induced nigrostriatal system damage . Consistent with those reports, we observed that MPTP-treated mice displayed a greater than 2-fold increase in the number of Iba1+ cells in their SNc. In contrast, mice that were treated with BCG prior to MPTP treatment had a similar number of SNC Iba1+ cells to that in saline-treated control mice. In addition, in BCG treated mice, the nigra microglia had small cell bodies and long ramified processes, indicating a resting state. Such microglia are thought to exert neurosupportive functions by their abilities to produce neurotrophins and eliminate excitotoxins. These observations parallel previous assessments of microglia in MPTP-treated mice that received an adoptive transfer of spleen cells from CopaxoneH/CFA vaccinated mice. However, our results show that peripheral BCG-induced immune responses are sufficient to almost completely inhibit the MPTP-induced increase in activated microglia number in the SNc. Conceivably, by circumventing the MPTP-induced increase in activated microglia and the accompanying proinflammatory milieu, the surviving dopaminergic neurons were better able to recover function in BCG-treated mice. Further studies will be necessary to establish how the marked alterations in microglia morphology and activation affect long-term nigrostriatal dopamine system integrity. Proposed mechanisms for neuroprotective vaccines have been contradictory in regard to whether Th1, Th2, Th3 and/or Treg cells play beneficial or pathogenic roles. Some of these differences may be due to the different disease models studied.
Focusing on studies of immune-mediated protection in the MPTP mouse PD model,vertical farm system recent studies have pointed to CD4+ T cells as playing a key role in neurodegeneration. Th17 cells recognizing nitrated a-synuclein can exacerbate MPTP-induced neuronal cell loss, but can be held in check by Tregs . The immune responses elicited by CFA and BCG have been extensively studied and they are both potent inducers of IFNc-secreting Th1-type CD4+ T cells and activators of antigen presenting cells.IFNc is known to antagonize the development of Th17 cells and can induce apoptosis of self-reactive T cells. Additionally, BCG or Mycobacterium tuberculosis infection induces Tregs that proliferate and accumulate at sites of infection, which contribute to limiting inflammatory responses and tissue damage during infection. Accordingly, the Th1 and Treg responses may have suppressed the priming and expansion of Teffector cells following MPTP treatment. It is possible that the robust T cell responses to BCG also created greater T cell competition for APC that reduced the priming of Teffector cells in the periphery. Another possible protective mechanism is that the active BCG infection in the periphery diverted Teffectors, macrophages and BMDC microglia precursors from entering the CNS after MPTP treatment. Previous studies in the experimental autoimmune encephalomyelitis model have shown that infection with BCG 6 weeks before the induction of EAE diverts activated myelin-reactive CD4+ T cells from the CNS to granulomas in the spleen and liver. This diversion was not due to cross-reactivity between BCG antigens and encephalitogenic proteins. Evidently, the peripheral inflammatory lesions non-specifically attracted Teffectors that blunted the development of EAE. Interestingly, in clinical trials, MS patients immunized with BCG had a 57% reduction of lesions as measured by MRI. Thus, there is some clinical evidence that BCG treatment can suppress a neurodegenerative autoimmune response.
Based on our observations that MPTP did not increase microglia number and that microglia were in a resting state in the nigra of BCG-vaccinated mice, it is possible that the BCG treatment circumvented the activation and replication of resident microglia, diverted macrophage or BMDC microglia precursors from entering the CNS, and/or induced some efflux of macrophage-type cells to the periphery. Another possible protective mechanism is that the long period during which the attenuated BCG slowly replicates in the host causes a long-term increase in the levels of circulating immune factors , many of which can enter the CNS. These immune factors may have limited microglia activation and proliferation, the influx of peripheral macrophages or microglia precursor cells, or had a supportive effect on neurons in the area of injury. Further testing is required to distinguish among these possibilities. There are additional lines of evidence that peripheral immune responses can modulate the CNS milieu. Many studies have shown that treatment of pregnant rodents with immuno-stimulants such as lipopolysaccharide, polycytidylic acid, turpentine or viral infection, cause the offspring to have behavioral abnormalities . It is thought that the maternal immune responses to these treatments can alter neurodevelopment in the fetus. These studies provide further evidence that peripheral immune responses can modulate the CNS milieu independently of CNS-reactive T cells. While the exact mechanisms of BCG neuroprotection in the MPTP mouse model remain to be elucidated, our results suggest that peripheral BCG-induced immune responses can exert neuroprotective effects independent of CNS antigen-specify. This represents a paradigm shift from the current notion that neuroprotective vaccines work by inducing protective T cell autoimmunity that acts locally in damaged areas in the CNS. It will be of interest to transfuse GFP-marked BMDC and T cells into mice prior to BCG and MPTP treatments in order to further study BCG’s protective mechanisms.
BCG vaccinations were discontinued in the USA in the 1950s largely because of the low incidence of TB and the vaccine’s incomplete protection. However, BCG vaccination is still given to infants and children in many countries. Adults who were BCG vaccinated as children have little/no protection from TB. Because BCG vaccine effects have greatly diminished by middle age, we would not expect to find a relationship between childhood BCG vaccination and PD incidence. Moreover, the BCG vaccine-mediated protection from TB relies on a small population of memory T cells that is quiescent and that only expands after re-exposure to TB. Since PD patients are not normally exposed to active TB, their few BCG-reactive memory T cells should be quiescent and would not be a source of neuroprotective factors. While neuroprotective vaccines cannot correct basic intrinsic neuronal deficits,vertical indoor farming they may alter the CNS environment to be more neurosupportive so that neurodegeneration and secondary damage to neurons progresses at a slower rate. Conceivably, BCG induced neuroprotective immune responses will be more beneficial in a slowly progressing disease, as in human PD, than in the acutely neurotoxic MPTP model we have studied. In summary, our data show that BCG vaccination, which is safe for human use, can preserve striatal dopaminergic markers. This strongly supports the notion that peripheral immune responses can be benifical in neuropathological conditions. Second generation recombinant BCG vaccines, which have greater immunogenicity and are expected to elicit enhanced immunity against TB, are now being tested in clinical trials. Some new recombinant BCG strains express a human cytokine to boost desired immune responses. It will be of interest to test whether different recombinant BCG strains can enhance the vaccination’s neuroprotective effects. Further studies of how peripheral immune system responses can modulate neurons and glia in the CNS may provide new therapeutic strategies to safely slow neurodegenerative disease processes.This study focuses on the California Department of Corrections and Rehabilitation , which is responsible for the care and custody of incarcerated individuals in the state of California who have been sentenced to terms greater than one year. Individuals sentenced to terms less than a year, or those awaiting sentence, are under the care of different entities: the county or regional jails. In contrast to the state’s other custodial systems, CDCR is distinguished by its long-term focus on the care and control of individuals. This impacts the development of policy that promotes structural permanence. A policy focus of this type presents a significant obstacle for change management and process management, two key elements required for program-implementation success that was required within CDCR. The agency was brought under federal receivership to improve health care outcomes for prisoners; a change that enabled the federal courts to demand the implementation of health programs aimed at improving health care outcomes.
The prison system in California consists of 33 separate facilities serving over 175,000 inmates in a system designed for no more than 100,000 inmates. Due to the “three-strikes rule,” a law that requires third-time felons be sentenced to prison terms, many of the state’s 33 correctional facilities were operating at over 200% of designed capacity. Additionally, by the end of calendar year 2008, the average age of prisoners was 37 years old. This represents an increase of 37% in the average age over a 28-year time span: in 1980 the average age of the incarcerated was 27. Overcrowding in the system, combined with upwardly spiraling costs, led to organizational failure. Inmates typically have more health issues than do those in the non-incarcerated population. An examination of de-identified CDCR data reveals that approximately 70% of the inmate population was taking at least one medication in the year 2009. The average for the U.S. population is closer to 47% . Aging inmates cost two to three times as much to incarcerate as younger prisoners—on average $98,000 to $138,000 a year . When inmates are paroled, they do not receive the same access to health care as they do while imprisoned. In the state of California, inmates had a 63.7 percent three-year recidivism rate as measured in fiscal year 2012 . While under custodial care, health care is free. Individuals reentering the prison system with medical conditions that were not treated while paroled may exhibit exacerbation in their medical conditions. The costs related to the treatment of individuals with more severe conditions are higher than they otherwise would have been if the individuals had received continuous care. In the absence of proactive treatments, and with an aging population in an overcrowded and unsafe environment, the costs associated with health care are likely to continue to rise among these wards of the state. The public health concerns go beyond the cost-of-care issue and are related to high recidivism rates and community health issues, including the spread of communicable diseases such as AIDS . Some of the most prominent failures within the CDCR system were avoidable inmate patient deaths, believed to have resulted from poor systems and controls related to the delivery of health care. A receivership was established as the result of a federal class-action suit, Plata v. Schwarzenegger , under which it was found that CDCR was deficient in providing constitutionally acceptable levels of medical care to prison inmates.Several federal court cases concerning unconstitutional conditions within the system preceded the institution of this receivership . Under Plata v. Schwarzenegger , it was found that, on average, one inmate-patient died every six to seven days as the result of deficiencies in the state prison’s health care system. The receiver was given all powers vested by law in the Secretary of the California Department of Corrections and Rehabilitation, including the administration, control, management, operation, and financing of the California prisons’ medical health care system. Thus the court placed full accountability for inmate health care in the hands of the receiver , giving the ability and responsibility to change the system according to court requirements. The receiver recruited a diverse team of industry experts consisting of medical, nursing, clinical quality, information technology, and facility construction professionals to assist with the prison health care reform efforts.CDCR is presently the second-largest law enforcement department in the nation and is the single largest state-run prison system in the United States . Over the past decade, this corrections agency has grown from the state of California’s third largest employer to the second, behind only the state’s University of California system . For fiscal year 2011, $9.5 billion was budgeted by CDCR in order to supervise and oversee over 300,000 of the state’s criminals found guilty in a court of law . This size and structure relates to the common perception of big-government bureaucracy. Large, bureaucratic organizations are unwieldy and difficult to change. Max Weber pointed out, “once it is fully established, bureaucracy is among those social structures which are the hardest to destroy” . This is true due to bureaucracy’s cohesiveness and discipline, its control of the facts, and its single-minded concentration on the maintenance of power.