bridging the gap between vaccination with bacille calmette ... · (bcg) and immunological...
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Bridging the gap between vaccination with BacilleCalmette-Guerin (BCG) and immunological tolerance:the cases of type 1 diabetes and multiple sclerosisGiovanni Ristori1,5, Denise Faustman2,5, Giuseppe Matarese3,5,Silvia Romano1 and Marco Salvetti1,4
Available online at www.sciencedirect.com
ScienceDirect
At the end of past century, when the prevailing view was that
treatment of autoimmunity required immune suppression,
experimental evidence suggested an approach of immune-
stimulation such as with the BCG vaccine in type 1 diabetes (T1D)
and multiple sclerosis (MS).Translating these basic studies into
clinical trials, we showed the following: BCG harnessed the
immune system to ‘permanently’ lower blood sugar, even in
advanced T1D; BCG appeared to delay the disease progression
in early MS; the effects were long-lasting (years after vaccination)
in both diseases.The recently demonstrated capacity of BCG to
boost glycolysis may explain both the improvement of
metabolic indexes in T1D, and the more efficient generation of
inducible regulatory T cells, which counteract the autoimmune
attack and foster repair mechanisms.
Addresses1Center for Experimental Neurological Therapies, Sant’Andrea Hospital,
Department of Neurosciences, Mental Health and Sensory Organs,
Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa
1035, 00189 Rome, Italy2 Immunobiology Department, Massachusetts General Hospital and
Harvard Medical School, Boston, MA 02129, USA3Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie
Mediche, Universita di Napoli ‘Federico II’, IEOS-CNR, Via S. Pansini 5,
80131 Napoli, Italy4 IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed,
86077 Pozzilli, IS, Italy
Corresponding authors:
Ristori, Giovanni ([email protected]),
Salvetti, Marco ([email protected])5 Equal contribution.
Current Opinion in Immunology 2018, 55:89–96
This review comes from a themed issue on Autoimmunity
Edited by Stetson
https://doi.org/10.1016/j.coi.2018.09.016
0952-7915/ã 2018 Published by Elsevier Ltd.
BCG vaccine in neuroinflammation: multiplesclerosis and beyondThe rationale for the use of adjuvant therapy in Experi-
mental Allergic Encephalomyelitis (EAE) dates back to
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the sixties [1]. Throughout the next 30 years we and
others obtained several results that reinforced the ratio-
nale, contradicting, at least in part, certain beliefs or
paradigms on autoimmune disorders. In particular the
following evidence prompted us to translate this approach
in human neuroinflammation: the resistance to EAE
induction by the pre-immunization with diverse antigens
(both non-self and auto-antigens) [2]; the immune devia-
tion toward a T helper 1 cytokine profile (considered
pathogenic) in multiple sclerosis (MS) patients with a
satisfactory response to interferon beta therapy [3]; the
‘physiological’ role of molecular mimicry, at least in T cell
responses [4,5]; the safety of influenza and other vaccines
in MS [6,7].
We studied the effect of BCG vaccine in patients with
early MS. A single cross-over magnetic resonance imaging
(MRI)-monitored trial [8] was performed on 14 partici-
pants. Comparing monthly MRI scans of pre-vaccination
and post-vaccination period we found that MRI activity,
expressed as gadolinium (Gd)-enhanced lesions plus new
and enlarging lesions in T2-weighted (T2W) images,
significantly dropped after BCG. No major adverse events
were reported [9��].
In this same cohort of MS patients we evaluated the
effect of BCG vaccine on the evolution of new Gd-
enhancing lesions to hypointense lesions on T1-
weighted MRI images through three new MRI scans
over 24 months after vaccination [10]. This allowed to
quantify the so-called black holes (BH), expression of
irreversible tissue damage, to evaluate the vaccine influ-
ence on axonal loss, that underlies the development of
clinical disability [11]. Once again we compared the two
phases of the trial (the run-in versus the post-BCG
percentage of NEL that evolve into BH), and found a
significant result: new enhancing lesions at MRI per-
sisted less and less frequently evolved to black holes
after the BCG vaccine. This post-hoc analysis seemed to
indicate that vaccination with BCG might decrease the
tissue damage. Moreover, the dynamics of BCG effects
over time prompted us to hypothesize its long-term
benefit and to design subsequent studies on a longer
temporal scale.
The suggestion found confirmation in a third study on
subjects with the first demyelinating episode (usually
Current Opinion in Immunology 2018, 55:89–96
90 Autoimmunity
referred to as clinically isolated syndrome—CIS), that is
considered, in the presence of a brain and spinal cord MRI
compatible with MS, the onset of clinical disease [12]. In
these parallel groups trials we met several significant end
points after a single vaccination with BCG in people with
CIS: reduced disease activity with MRI monitoring, less
propensity to develop black holes at 18 months, lower
occurrence of the second demyelinating event (that is
conversion to clinically definite MS) at 60 months, with-
out major adverse event due to vaccine (Figure 1) [13��].
Underway currently is our trial with the BCG vaccine in
people with ‘radiologically isolated syndromes’ (RIS): a
new subclinical entity, that occurs when an MRI of the
central nervous system shows results compatible with
MS, but without any symptom or sign of disease [14].
The trial stemmed from reasoning that safe and manage-
able approaches, that can be used with the (biological)
onset of the disease, are important unmet needs in MS. In
fact, the last-decade therapeutic progress for the overt
relapsing-remitting form was reached at the cost of safety,
quality of life and overtreatment. Being safe, cheap and
available, the BCG vaccine seemed appropriate as a front-
line immune-modulatory approach for people with RIS.
Figure 1
Cu
mu
lati
ve s
urv
ival
of
free
rel
apse
Baseline-month 6 Baseline-month 12 Baseline-month 18
Mea
nch
ang
es(±
SE
M)
in t
ota
l T-1
hyp
on
ten
sele
sio
ns
incl
ud
ing
‘bla
ckh
ole
s’
(a)
Placebo
BCG
2
1,0
0,8
0,6
0,4
(b)
1
0
Long-term effects of a single BCG vaccination in people with first demyelin
including ‘black holes’ that express irreversible tissue damage, over 18 mon
is not converting to clinically definite multiple sclerosis) over 60 months.
Current Opinion in Immunology 2018, 55:89–96
The mechanisms of action of BCG vaccine in MS are
not clear. However, clinical observations along with
genetic and functional studies suggest a net beneficial
role of TNF in human neuroinflammation, that may be
deficient in MS patients, and seems to be at variance
with more complex effects seen in EAE [15]. In fact,
diseases worsening occurred when therapies antagoniz-
ing tumor necrosis factor (TNF) were tried in MS [16],
contrary to other autoimmune disorders where anti-
TNF is beneficial, but bears risks of demyelinating
episodes. Moreover, an MS-associated genetic variant
directs increased expression of a soluble protein that
acts as an analogous of anti-TNF agents [17]; notably,
this variant is not associated with autoimmune disorders
where TNF antagonism results beneficial. A potent
TNF inducer, such as BCG vaccination, may be useful
to rescue TNF deficit in MS, and this is in keeping with
evidences coming from type 1 diabetes (see next
section).
Another promising field for adjuvant approach seems to
be that of more common neurological disorders, such as
Alzheimer’s and Parkinson disease, classically considered
of degenerative nature. Recent evidences consistently
Follow-up (months)
placebo + DMTBCG + DMT
0 10 20 30 40 50 60
Current Opinion in Immunology
ating episode. (a) Mean change in the total T1-hypointense lesions,
ths. (b) Proportion of people free from the second clinical event (that
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Bridging the gap between vaccination with Bacille Calmette-Guerin (BCG) and immunological tolerance Ristori et al. 91
showed a neuroinflammatory component in these dis-
eases, with a prevalent role for glial cells and innate
immune system [18]. In this context a neuroprotective
action of BCG vaccine emerged in experimental models
of neurodegenerative diseases. Two works in models of
PD suggested a BCG-mediated immune stimulation, that
may limit deleterious microglial response to a neuronal
insult [19�], may promote T regulatory protective
responses [20]. Other two works in models of AD eluci-
dated additional mechanisms of neuroprotection: activa-
tion of tumor necrosis factor receptor 2 (TNFR2), that
block neuroinflammation and promote neuronal survival
[21], as well as recruitment of inflammation-resolving
monocyte (producing anti-inflammatory cytokines and
neurotrophic factors) at the choroid plexus and perivas-
cular spaces of plaque pathology [22]. Along the same line
of research several works showed a beneficial effect of
neonatal BCG vaccination on neurodevelopment and on
counteracting neurobehavioral impairment and neuroin-
flammation due to secondary immune challenge in adult
mice [23,24].
BCG and type 1 diabetes
Our 20-year journey towards using BCG to treat type
1 diabetes (T1D) started off in a paradoxical direction.
Studying both human and mouse models, we discovered T-
lymphocyte (T cell) imbalances, both an overabundance of
pathogenic cytotoxic T cells (CD8 CTLs), and a paucity of
suppressive T-regulatory (CD4 Treg) cells. Importantly
these immune cell imbalances could be corrected with
tumor necrosis factor (TNF), a well-known pro-inflamma-
tory cytokine with immune-stimulatory properties. At the
time, however, the prevailing view was that treatment of
T1D and other forms of autoimmunity required immuno-
suppression, not immunostimulation, the same belief that
also dominated the multiple sclerosis field.
Through basic science, we discovered that the antigen-
presenting cells of T1D patients had interruptions in CD8
T cell education due to a paucity of self-peptides being
generated for the HLA class I groove, a process controlled
by intracellular processing in antigen-presenting cells [25�
,26,27]. This was some of early T1D data implementing
CD8 T cells in the disease; prior studies thought CD4 T
cells were the central cells in T1D. The intracellular
antigen presenting process normally utilized the TAP
and proteasome genes and this presentation of self antigens
was altered in T1D. Interestingly these HLA class I pre-
senting genes were located in the high-risk HLA region
[28–33]. Our research suggested that HLA class I presen-
tation of self-proteins was necessary for tolerance [30]. With
proteasomedysfunction, additional intracellularprocessing
defects were also detected in T1D. NFkB activation, a
proteasome-dependent process for T cell education path-
ways, was also dysfunctional [34,35]. TNF is the cytokine
that normally stimulates theNFkB signaling pathway. This
TNF-stimulated pathway promotes antigen presentation,
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T cell maturation and proper education of T cells. Interrupt
of this pathway would be predicted to cause autoimmunity.
If there was perhaps too little TNF or at least sluggish
TNF-mediated signaling in the immune system, could
something as simple of adding back TNF be therapeutic
for T1D? Indeed, TNF selectively killed autoreactive T
cells causing T1D and multiple sclerosis and also in other
autoimmune diseases such a multiple sclerosis antigen
presenting defects in HLA class I have been reported
[36–39]. The data started to accumulate that this inflam-
matory cytokine, TNF might be therapeutic. Animal mod-
els of autoimmunity also demonstrated the therapeutic
benefit of TNF. Disease causing cytotoxic T cells, har-
vested from the spleens of diabetes affect mice, normally
transfer disease to naıve animals. If these splenocytes were
first in vitro treated with TNF, disease transfer was pre-
vented [36]. TNF itself or TNF induction with the BCG
vaccine was found to prevent onset as well as reverse even
end-stage disease in the NOD mouse model when admin-
istered in vivo [40,41]. This suggested that autoimmune
diseases needed TNF, not immunosuppression, as a ther-
apeutic approach (Figure 2). As further refinements of
these experiments continued, TNF or TNF stimulation
through the TNFR2 receptor was the central pathway for
disease modification [42,43].
Translating these basic studies into clinical trials of T1D
could be accomplished by two routes: manufacture and
start a TNF drug program (TNFR2 agonistic antibodies
were not available at the time) or develop and recycle a
safe 100 year-old drug, BCG, an inactive version of
Mycobacteria bovis originally developed to protect from
tuberculosis and a known inducer of TNF. Because of
monetary limitations, we decided to launch a T1D trial
with BCG as a method to induce and restore TNF.
In 2012, we published the Phase I results from multi-
dosing BCG in long-term T1Ds (>10 years disease dura-
tion) [44��]. This was a safety trial that also studied
important biomarkers of efficacy. We established that
BCG was safe in this patient population, and showed
consistent trends with the proposed mechanism of action
of BCG: death of autoreactive T cells, induction of Tregs,
and minor increase of C-peptide secretion (a marker of
insulin production by the pancreas), suggesting some
restored activity [44��]. In support of BCG in T1D, an
epidemiology study from Turkey has since showed that
multi-dosing BCG may not only be beneficial in T1D
treatment, but also in its diabetes prevention. Participants
who received greater than 2 childhood vaccines of BCG
had diminished lifelong risk for developing T1D [45].
Our 12-week-long Phase 1 trial showed that C-peptide
production was not increased in a clinically meaningful
way, although seeing any restored C-peptide in T1D with
this long standing disease was unusual. We asked, had we
followed our patients long enough? We subsequently
Current Opinion in Immunology 2018, 55:89–96
92 Autoimmunity
Figure 2
Treg
BCG
TNF
Treg
Treg
Treg
Treg
Treg
Treg
CTL
TL
CTL
CTLCTL
CTL
CTL
CTL Cytotoxic T cell
Unhealthy Treg
CTL
Treg Activated TNFR2 Treg
Autoimmune target tissue
CTL
CTL
CTL Cytotoxic T cells
Current Opinion in Immunology
Immune mechanisms for the action of TNF induction through BCG. BCG through direct TNF induction or TNFR2 agonism on infected antigen
presenting cells can directly and selectively kill cytotoxic T cells and proliferate Treg cells, thus re-establish immune tolerance.
learned from the multiple sclerosis trials by Ristori et al. that
BCG’s benefit, while slow to start, showed measurable
disease improvement over the next 2–3 years. With this
in mind, we re-opened our Phase I trial to follow our T1D
patients for another 8 years. Similar to the timeframe with
multiple sclerosis, we found that, by year 3, blood sugar
began to drop and hemoglobin A1c (HbA1c) gradually
returned to near normal levels. This slow-to-materialize,
but remarkable, correction of blood sugars towards normal
by BCG persisted for 5 more years [46��]. Repeat BCG
vaccines were a powerful way to harness the immune
system and alter metabolism to ‘permanently’ lower blood
sugars, even in advanced TID. In 2018, we showed that the
mechanism for better blood sugar control by BCG was due
to a systemic shift in metabolism from oxidative phosphor-
ylation to aerobic glycolysis, a metabolic state with accel-
erated transport and utilization of serum sugar for energy.
BCG therapy in human autoimmunity thus opened up the
exciting possibility of a safe and an effective vaccine for
resetting the immune system even in existing T1D disease
states. The BCG vaccine confirmed and verified an entirely
novel way to regulate blood sugars. Fully enrolled and
ongoing human clinical trials continue to test the validity
of BCG lowering of blood sugars in large patient popula-
tions and unlike most immune intervention trials is T1D,
the BCG vaccine was potent enough to have these
Current Opinion in Immunology 2018, 55:89–96
beneficial clinical effects in patients with long standing
diabetes. Before this time, immune interventions were
exclusively tried in only new onset T1D, a clinical setting
thought easier to reverse.
Immunometabolic effects of BCG inautoimmunityBCG, as therapeutic opportunity to induce immunologi-
cal tolerance, is a very attractive one. At mechanistic level,
despite compelling experimental evidence suggests the
capacity of BCG to affect immune responses, the cellular
and molecular determinants controlling this process are
still not fully understood. Originally, BCG was considered
a powerful tool to stimulate immunity against Mycobacte-rium tuberculosis (MTB); indeed BCG infection is charac-
terized by a classical strong induction of Th1/Th17
responses in immunized individuals, able to exert protec-
tion against MTB infection, particularly in very young
individuals. The induction of this type of response is in
‘apparent contrast’ with the capacity of BCG to protect
from induction of mouse EAE and the development of
T1D in the NOD mouse, both models of disease caused
by pro-inflammatory Th1/Th17 switches [47,48].
A possible explanation for this ‘apparent paradox’ comes
from recent studies linking immunometabolic pathways
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Bridging the gap between vaccination with Bacille Calmette-Guerin (BCG) and immunological tolerance Ristori et al. 93
to the capacity of BCG to induce glycolysis in T cells and
innate immune cells such as monocytes/macrophages
[49��]. Glycolysis fuels proliferation and differentiation
of CD4+T cells towards Th1 and Th17 responses, but it is
also necessary to generate specific populations of induc-
ible regulatory T cells (iTreg) cells from conventional T
(Tconv) cells in humans [50�]. While differentiated Treg
cells show a mixed metabolic profile being able to engage
both glycolysis and lipid oxidation, engagement of
Figure 3
Treg cells
Glycolysis
Tconv cells
(a)
(b)
Auto Ag-TCRstimulation
Tconv cells
Auto Ag-TCRstimulation
ProliferatingTconv cells
Induction of Treg cellsControl of pathogenic effector
Th subsets
Th1 ce
Treg cells
BCGvaccination
High glycolysis
ProliferatingTconv
Th17 ceLow induction of Treg cells andconsequent higher generation
of pathologic effector Th subsets
Hypothetical pro-tolerogenic capacity of BCG vaccination via enhancement
is a reduced engagement of glycolysis in Tconv cells which leads to reduce
Th1/Th17 responses. (b) BCG vaccination is able to boost engagement of g
increase iTreg cell generation which in turn control pro-pathogenic Th1/Th1
deleterious microglial response to a neuronal insul
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glycolysis appears to be necessary to generate iTreg cells
from Tconv cells [50�,51�]. Specifically, this process
appeared tightly linked with the timing and strength of
T cell receptor (TCR) engagement; indeed only TCR
stimulation determined a consistent engagement of gly-
colysis able to sustain the appropriate induction and
maintenance overtime of the Foxp3 gene, whose expres-
sion is crucial for Treg cell maintenance and suppressive
functions [50�,51�,52�].
Th1 cells
Damage
Damage
Central nervous system
Pancreatic-cells
Pancreatic-cells
Autoimmunity
lls
Th17 cells
Immune tolerance
lls
Central nervous system
Current Opinion in Immunology
of glycolysis. (a) In autoimmune disorders such as MS and T1D there
d iTreg cell induction and consequent enhancement of pro-pathogenic
lycolysis in Tconv cells upon TCR activation and consequently
7 responses.
Current Opinion in Immunology 2018, 55:89–96
94 Autoimmunity
It is also interesting to note that autoimmune disorders
such as MS and T1D associate with reduced engagement
of glycolysis by T cells [50�,53��]. From these consider-
ations, it is possible to speculate that glycolysis is part of
a ‘double edged’ process in which while effector
responses towards BCG require glucose oxidation to
warrant Th1/Th17 differentiation, also iTreg cells gen-
erate in the same process, whose function is necessary to
control the inflammatory process and avoid possible
‘collateral damage’ during inflammation driven by
BCG infection. Thus, with this view, immunological
tolerance could be considered as an inducible process
during ongoing immune responses, and thus infections
and inflammatory processes that consistently engage
glycolysis warrant also a better induction of Foxp3+ T
cells which in turn control inflammation and tissue
damage (Figure 3). These cells, can contribute to
improvement of inflammation in autoimmune diseases
such as MS and T1D, but also could enhance tissue-
remodeling and regeneration in both myelin and beta-
cells, through mediators such as TGF-b. It is clear that
further research is needed to better dissect at cellular
and molecular level this hypothesis, but the ongoing
direction of current basic and pre-clinical research is
highly suggestive of this novel concept.
We ‘converged’ on the clinical evaluation of BCG in MS
and T1D from different premises. This is remarkable, as
it supports the broad rationale that a benign exposure to
microbes (especially the ‘old friends’ that have co-
evolved with human beings for millennia) [54] may help
antagonize conditions sharing chronic inflammation and
tissue damage. The beneficial effect of BCG vaccination,
at least in some autoimmune disorders, adds an intriguing
viewpoint for studying the host-microbe interplay in the
pathophysiology and treatment of immune-mediated
diseases.
Conflict of interest statementNothing declared.
AcknowledgementsWe thank Fortunata Carbone for figures.
Fundings: GM is supported by the European Research Council“menTORingTregs” grant no. 310496, the Fondazione Italiana SclerosiMultipla grant no. 2016/R/18 and the Telethon grant no. GGP17086. GR issupported by Fondazione Italiana Sclerosi Multipla, grant no. 2016/S/1. DLF is supported by The Iacocca Foundation.
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28. Ma L, Penfornis A, Wang X, Schoenfeld D, Tuomilehto-Wolf E,Metcalfe K, Hitman G, Faustman D: Evaluation of TAP1polymorphisms with insulin dependent diabetes mellitus inFinnish diabetic patients. The Childhood Diabetes in Finland(DiMe) Study Group. Human Immunology 1997, 53:159-166.
29. Yan G, Shi L, Fu Y, Wang X, Schoenfeld D, Ma L, Penfornis A,Gebel H, Faustman DL: Screening of the TAP1 gene bydenaturing gradient gel electrophoresis in insulin-dependentdiabetes mellitus: detection and comparison of newpolymorphisms between patients and controls. TissueAntigens 1997, 50:576-585.
30. Faustman D, Li X, Lin HY, Huang R, Guo J: Expression of intra-MHC transporter (HAM) genes and class I antigens indiabetes-susceptible NOD mice. Science 1992, 256:1830-1831.
31. Faustman D: Faulty major histocompatibility complex class Ifunction linked to autoimmune diabetes. Transplant Proc 1992,24:2874-2876.
32. Yan G, Fu Y, Faustman DL: Reduced expression of Tap1 andLmp2 antigen processing genes in the nonobese diabetic
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(NOD) mouse due to a mutation in their shared bidirectionalpromoter. J Immunol 1997, 159:3068-3080.
33. Fu Y, Yan G, Shi L, Faustman D: Antigen processing andautoimmunity. Evaluation of mRNA abundance and function ofHLA-linked genes. Ann N Y Acad Sci 1998, 842:138-155.
34. Hayashi T, Faustman D: NOD mice are defective in proteasomeproduction and activation of NF-kappaB. Mol Cell Biol 1999,19:8646-8659.
35. Hayashi T, Faustman D: Essential role of human leukocyteantigen-encoded proteasome subunits in NF-kappaBactivation and prevention of tumor necrosis factor-alpha-induced apoptosis. J Biol Chem 2000, 275:5238-5247.
36. Kodama S, Davis M, Faustman DL: The therapeutic potential oftumor necrosis factor for autoimmune disease: amechanistically based hypothesis. Cell Mol Life Sci 2005,62:1850-1862.
37. Li F, Hauser SL, Linan MJ, Stein MC, Faustman DL: Reducedexpression of peptide-loaded HLA class I molecules onmultiple sclerosis lymphocytes. Ann Neurol 1995, 38:147-154.
38. Hayashi T, Faustman DL: Implications of altered apoptosis indiabetes mellitus and autoimmune disease. Apoptosis 2001,6:31-45.
39. Kuhtreiber WM, Hayashi T, Dale EA, Faustman DL: Central role ofdefective apoptosis in autoimmunity. J Mol Endocrinol 2003,31:373-399.
40. Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL: Reversalof established autoimmune diabetes by restoration ofendogenous beta cell function. J Clin Invest 2001, 108:63-72.
41. Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL: Isletregeneration during the reversal of autoimmune diabetes inNOD mice. Science 2003, 302:1223-1227.
42. Okubo Y, Mera T, Wang L, Faustman DL: Homogeneousexpansion of human T-regulatory cells via tumor necrosisfactor receptor 2. Sci Rep 2013, 3:3153.
43. Okubo Y, Torrey H, Butterworth J, Zheng H, Faustman DL: Tregactivation defect in type 1 diabetes: correction with TNFR2agonism. Clin Transl Immunol 2016, 5:e56.
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Faustman DL, Wang L, Okubo Y, Burger D, Ban L, Man G,Zheng H, Schoenfeld D, Pompei R, Avruch J, Nathan DM: Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes.PLoS One 2012, 7:e41756.
This is the first paper showing the value of multi-dosing BCG in type1 diabetes with the drug inducing cytoxoxic T cell death, inducing Tregcells and also restoring a very tiny amount of insulin secreting from thepancreas.
45. Karaci M: The protective effect of the BCG vaccine on thedevelopment of type 1 diabetes in humans. The Value of BCGand TNF in Autoimmunity. edn 1. Academic Press; 2014:52-62.
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Kuhtreiber WM, Tran L, Kim T, Dybala M, Nguyen B, Plager S,Huang D, Janes S, Defusco A, Baum D et al.: Long-termreduction in hyperglycemia in advanced type 1 diabetes: thevalue of induced aerobic glycolysis with BCG vaccinations.NPJ Vaccines 2018, 3:23 eCollection 2018.
This paper shows the first long term and safe reversal of blood sugars inT1D who received multiple doses of the BCG. T1D subject were eitherfollowed for 5 or 8 years showing the durability of the BCG reset of theimmune system and the permanent tolerance re-established at the genelevel with BCG.
47. Ben-Nun A, Mendel I, Sappler G, Kerlero de Rosbo N: A 12-kDaprotein of Mycobacterium tuberculosis protects mice againstexperimental autoimmune encephalomyelitis. Protection inthe absence of shared T cell epitopes with encephalitogenicproteins. J Immunol 1995, 154:2939-2948.
48. Qin HY, Singh B: BCG vaccination prevents insulin-dependentdiabetes mellitus (IDDM) in NOD mice after diseaseacceleration with cyclophosphamide. J Autoimmun 1997,10:271-278.
Current Opinion in Immunology 2018, 55:89–96
96 Autoimmunity
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Arts RJW, Carvalho A, La Rocca C, Palma C, Rodrigues F,Silvestre R, Kleinnijenhuis J, Lachmandas E, Gonc alves LG,Belinha A et al.: Immunometabolic pathways in BCG-inducedtrained immunity. Cell Rep 2016, 17:2562-2571.
This is a key report showing that BCG is able to boost glycolysis in T cells.
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De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M,Zuchegna C, Romano A, De Simone S, Procaccini C, La Rocca Cet al.: Glycolysis controls the induction of human regulatory Tcells by modulating the expression of FOXP3 exon 2 splicingvariants. Nat Immunol 2015, 16:1174-1184.
This is the first paper linking glycolysis engagement and induction of iTregcells in humans, particularly those containing the Foxp3 exon2 splicingvariants.
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Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V,Galgani M, Faicchia D, Marone G, Tramontano D, Corona M et al.:The proteomic landscape of human ex vivo regulatory andconventional T cells reveals specific metabolic requirements.Immunity 2016, 44:406-421.
This report, suggests that ex vivo human Treg cells engage glycolysis andwhen put in vitro change dynamically their metabolism engaging bothglycolysis and lipid synthesis.
Current Opinion in Immunology 2018, 55:89–96
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De Rosa V, La Cava A, Matarese G: Metabolic pressure and thebreach of immunological self-tolerance. Nat Immunol 2017,18:1190-1196.
This paper suggests metabolism as key novel determinant in the controlof immune tolerance to self.
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La Rocca C, Carbone F, De Rosa V, Colamatteo A, Galgani M,Perna F, Lanzillo R, Brescia Morra V, Orefice G, Cerillo I et al.:Immunometabolic profiling of T cells from patients withrelapsing-remitting multiple sclerosis reveals an impairmentin glycolysis and mitochondrial respiration. Metabolism 2017,77:39-46.
This is the first report showing that in MS there is a reduced engagementof glycolysis which is reversible by treatment with beta-interferon.
54. Reber SO, Siebler PH, Donner NC, Morton JT, Smith DG,Kopelman JM, Lowe KR, Wheeler KJ, Fox JH, Hassell JE Jr et al.:Immunization with a heat-killed preparation of theenvironmental bacterium Mycobacterium vaccae promotesstress resilience in mice. Proc Natl Acad Sci U S A 2016, 113:E3130-3139.
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