Bridging the gap between vaccination with Bacille Calmette ... · (BCG) and immunological...

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


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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

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Baseline-month 6 Baseline-month 12 Baseline-month 18

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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.


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


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,


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


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


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


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



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


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


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.


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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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


(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.

44.��

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.

46.��

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.






























































































































96 Autoimmunity

49.��

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.

50.�

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.

51.�

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.


52.�

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.

53.��

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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