Received: 18 May 2017

Revised: 9 August 2017

Accepted: 15 August 2017

DOI: 10.1002/dmrr.2941

REVIEW ARTICLE

TNF, TNF inducers, and TNFR2 agonists: A new path to type 1
diabetes treatment
Denise L. Faustman1,2
1

Director of Immunobiology, Massachusetts
General Hospital, Boston, MA, USA

2

Associate Professor of Medicine, Harvard
Medical School, Boston, MA, USA
Correspondence
Denise L Faustman, Massachusetts General
Hospital—East, Bld 149, 13th Street, Rm 3602,
Boston, MA 02129, USA.
Email: faustman@helix.mgh.harvard.edu

Summary
In the past decade, interest in the century‐old tuberculosis vaccine, bacillus Calmette‐Guerin(BCG), has been revived for potential new therapeutic uses in type 1 diabetes and other formsof autoimmunity. Diverse clinical trials are now proving the value of BCG in prevention andtreatment of type 1 diabetes, in the treatment of new onset multiple sclerosis and other immune
conditions. BCG contains the avirulent tuberculosis strain Mycobacterium bovis, a vaccine
originally developed for tuberculosis prevention. BCG induces a host response that is driven inpart by tumour necrosis factor (TNF). Induction of TNF through BCG vaccination or throughselective agonism of TNF receptor 2 (TNFR2) has 2 desired cellular immune effects: (1) selective
death of autoreactive T cells and (2) expansion of beneficial regulatory T cells (Tregs). In humanclinical trials in both type 1 diabetes and multiple sclerosis, administration of the BCG vaccine
to diseased adults has shown great promise. In a Phase I trial in advanced type 1 diabetes (meanduration of diabetes 15 years), 2 BCG vaccinations spaced 4 weeks apart selectively eliminatedautoreactive T cells, induced beneficial Tregs, and allowed for a transient and small restorationof insulin production. The advancing global clinical trials using BCG combined with mechanistic
data on BCGs induction of Tregs suggests value in this generic drug and possible immune reversalof the type 1 diabetic autoimmune process.
KEY W ORDS

autoimmunity, bacillus Calmette‐Guerin (BCG), regulatory T cells (Tregs), tumour necrosis factor(TNF), tumour necrosis factor receptor 2 (TNFR2), type 1 diabetes

1|

I N T RO D U CT I O N

few or poorly functioning regulatory T cells (Tregs), a subtype of T lymphocytes that help maintain tolerance to self‐antigens and suppress orAutoreactive T cells directed to diverse insulin‐secreting islet cell pro-

quiet the immune response, and too many cytotoxic T cells.1 This isteins are the predominant cause of type 1 diabetes, yet there are cur-illustrated as an alerted autoimmune microenvironment at the site ofrently no approved therapies that selectively target these self‐directed

autoreactivity (Figure 1).

cytotoxic T cells. Rather, immune‐directed treatments like immunosup-

Preclinical and clinical evidence suggests that the regulatory cyto-pressants and lymphocyte‐directed or cytokine‐directed antibodies

kine tumour necrosis factor (TNF), inducers such as bacillus Calmette‐that kill or harm autoreactive T cells also can produce undesirable

Guerin (BCG), or TNF receptor 2 (TNFR2) agonistic antibodies may

immune side effects in the host.

provide a pathway to targeted and selective destruction of the

There is evidence that type 1 diabetes and other, diverse forms ofautoreactive T cells in type 1 diabetes.2-4 In addition, this treatment

autoimmunity are diseases driven by immune imbalances due to too

approach may also provide clinical benefits by inducing Tregs thatsuppress pathologic T cells. TNF can directly and selectively kill the

Research sponsor: The Iacocca Foundation and other philanthropic dollars supported this research, including the James B Pendleton Charitable Trust, Friends
United for Juvenile Diabetes Research, and Partnership for Cures. No drug company or for‐profit resources supported this trial. The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of themanuscript.

Diabetes Metab Res Rev. 2017;e2941.
https://doi.org/10.1002/dmrr.2941

autoreactive T cells both in diabetes‐prone non‐obese diabetic (NOD)
mice as well as in humans with type 1 diabetes.5-7 Clinical trials in type1 diabetes and another autoimmune condition, multiple sclerosis, arecurrently investigating this strategy, especially as it relates to
medications that induce elevation of TNF levels. Therapies that could

wileyonlinelibrary.com/journal/dmrr

Copyright © 2017 John Wiley & Sons, Ltd.

1 of 6

2 of 6

FAUSTMAN

Treg

Treg

TNFR2 agonism

Treg

Teff-CD8

TNF
Teff-CD8

BCG

Treg

Treg
Teff-CD8

Teff-CD8

FIGURE 1 The autoimmune
microenvironment. At the tissue site inautoimmune diseases, there are too few Treg
cells and too many T effector cells or cytotoxic
T cells. The hypothesis of this review is that
TNF or TNFR2 agonism can alter thisabnormal microenvironment and convert it toa non‐disease stateboth expand Tregs and kill autoreactive autoreactive T cells such as has

this process is disrupted. NF‐κB cannot be activated to counteract

been suggested by TNFR2 agonism or TNF induction might be able to

TNF‐induced apoptosis, leaving the cell vulnerable to death. Inchange the autoreactive microenvironment of the disease siteexperiments performed in culture, in vitro cell death of a subpopulation(Figure 1).

of autoreactive CD8 T cells, but not CD4 cells, has been demonstrated

In this review, the role of the TNF pathway and the use of the BCG

by incubating TNF with blood samples from patients with type 1

vaccine and other TNF inducers or agonists as treatments fordiabetes and other autoimmune diseases known to have defects inestablished type 1 diabetes are discussed, focusing on recent humanthe NF‐κB pathway.5

data and supporting data from other autoimmune diseases.

Soluble TNF can bind to both TNF receptor 1 (TNFR1) and TNFR2,
although preferential binding is towards TNFR1, which is ubiquitously

1.1 | Signalling defects in the TNF pathway in type 1
diabetes make insulin‐autoreactive T cells vulnerable toapoptosis in the presence of elevated TNF or TNFR2
agonism

expressed, whereas TNFR2 is infrequently expressed in the normal

In type 1 diabetes, insulin‐autoreactive T cells mediate destruction ofand, therefore, sole engagement of TNFR1 results in cell death. By

the pancreatic beta cells that produce insulin, leading to insulin

contrast, sole engagement of TNFR2 causes normal CD8 T cells to

deficiency, hyperglycemia, and the need for lifelong insulin injections.

proliferate. This paradoxical response between engagement with

Despite1

TNFR1 and TNFR2 is due to both the activation state of the T cells

diabetes will develop disease‐related microvascular and macrovascularand that the TNFR2 receptors have very different TNF signallingcomplications, underscoring the need for new, effective interventions.

pathways. The TNFR1 intracellular domain is a cell death domain,

Directly addressing autoimmunity through interventions focused onwhereas the TNFR2 intracellular domain is linked to NF‐κB expansion.

the TNF pathway is a promising new approach that is currently being

In diseased CD8 T cells from autoimmune patients (which all express

investigated in human clinical trials.

TNFR2), TNF or TNFR2 agonism causes selective cell death throughinsulintreatment,

manypatients

with

type

immune system. The natural ligand for TNFR2 is trimeric membrane
TNF, most often expressed on monocytes. The engagement of TNF
with its receptors results in contrasting responses, depending on thereceptor. In non‐diseased cells, TNFR1 is linked to cell death pathways,

The rationale behind this approach is based on over 2 decades ofan altered signalling pathway. This ability of TNF or TNFR2 engage-

work that identified signalling defects in the NF‐κB pathway ofment to be selective for CD8‐driven cell death was functionally tested

autoimmune mice8,9 and then shown in mice and humans that thesein the human disease setting of type 1 diabetes and other autoimmune

intracellular signalling errors in insulin‐autoreactive T cells make themdiseases. Fresh autoimmune CD8 T cells from autoimmune patientsselectively vulnerable to death upon exposure to or induction ofwere incubated with either TNF, TNFR1 agonistic antibodies, or

5,7,10,11

In addition, TNFR2 agonism has also been shown to

TNFR2 agonistic antibodies. The human autoimmune data were clear:effectively and selectively kill insulin‐autoreactive CD8+ T cells in

only TNFR2 agonists, but not TNFR1 agonists, had the ability to target

blood samples taken from patients with type 1 diabetes.5

and kill the autoreactive T cells from diverse human autoimmune

TNF.

Autoreactive T cells, but not normal T cells, are selectively

diseases, including cytotoxic T cells in type 1 diabetes, as well as

vulnerable to TNF‐induced apoptosis. This is a result of genetic or

autoimmune cells in multiple sclerosis, Graves' disease, Crohn'sfunctional defects that prevent the transcription factor signalling indisease, and other forms of autoimmunity.5 Additionally, murine

the NF‐κB pathway, thereby preventing this pro‐life survival factor

autoimmune data show that TNF, TNF induction, and TNFR2 agonism

from entering the nucleus to express pro‐survival genes. In normal T

all relieve the burden of autoreactive cells by selectively inducing cell

cells, TNF activates the proteasomal cleavage of NF‐κB from IKBα.

death and also prevent disease transfer.12,13 Of the 2 receptors that

After

initiates

TNF acts upon, TNFR2 has more limited cellular expression and istranscription of an array of anti‐apoptotic proteins that counteract

cleavage,

NF‐κB

entersprimarily expressed on T cells, subsets of neurons, and a few other cell12

the pro‐apoptotic effects of TNF.

thenucleusandThus, NF‐κB activation in normal

types such as Tregs and diseased cytotoxic T cells. TNFR1's morecells is protective, preventing cells from death upon TNF exposure.

ubiquitous expression, which correlates with toxicity data, even in

Conversely, in type 1 diabetes and some other forms of autoimmunity,

baboons, suggests that TNFR2 agonism would be expected to have a3 of 6

FAUSTMAN

better toxicology profile. In patients with type 1 diabetes, theBCG or its heat‐inactivated equivalent, complete Freund's adjuvant

subpopulation of T cells vulnerable to TNF or TNFR2 agonist‐induced(CFA). Like many other interventions, BCG and CFA can prevent type

death was traceable to insulin‐autoreactive CD8 T cells.5

1 diabetes onset if administered to young NOD mice.21-25 What

Overall, signalling defects through the TNF pathway, whether

distinguishes BCG and CFA from many other forms of immunotherapy

through NF‐κB or activators of NF‐κB, such as the proteasomein mice, however, is that BCG and CFA not only can stop new‐onset

complex and the ubiquitination process, may provide an importantdiabetes, they can also reverse end‐stage diabetes.11,26 Data in animal

opportunity for intervention in type 1 diabetes.

models have shown that double dosing of BCG was more effective
than single dosing in preventing diabetes onset in NOD mice.27 In

1.2 | Induction of TNF or TNFR2 agonism triggers
expansion of Tregs

addition, for BCG or CFA to be effective in the NOD mouse model,
the immune adjuvant needed to be administered after the autoimmune
disease had started the attack in the pancreas. If BCG, CFA, or TNF

In addition to eliminating the autoreactive cells, TNF induction or

was administered at birth into NOD mice, disease prevention did not

TNFR2 agonism may work through a second mechanism, by triggering

occur, and some data have shown that BCG administered at birth in

the induction or expansion of Tregs. Tregs are a subset of CD4 T

the mouse could accelerate disease expression.28 The NOD

cells that help to prevent or treat autoimmunity by maintaining self‐mouse data also show in NOD mice‐administered CFA, BCG, or

tolerance, immune homeostasis, and suppression of cytotoxic T cells.1

TNF‐upregulated Tregs appeared in treated mice a potential benefit

However, clinical application of Tregs in autoimmunity has been

due to the possible disease‐reversing effects due to the induction of

hampered by the difficulty in obtaining and safely applying sufficientthese suppressive Treg expansion.29,30
Unlike many other “cures” of type 1 diabetes in mice, BCG or CFA

quantities of Tregs, whether generated in vitro or stimulated in vivo,
to be effective.

prevented or reversed type 1 diabetes while imposing little or no

In humans with longstanding type 1 diabetes, repeat BCG

toxicity. Although the mechanism for efficacy is mediated throughadministration (2 doses) induced proliferation of Tregs in a Phase I

TNF, systemic toxicity prevents the use of direct TNF administration

clinical trial,14 which appeared to contribute to early clinical benefits

at high doses in the human. However, TNF induction with a safe

including suppression of disease and transient restoration of low‐levelvaccine such as the BCG vaccine or via TNFR2 agonism may be ainsulin secretion.

way to correct signalling defects and address autoimmunity throughSimilar to BCG vaccinations, TNFR2 agonism induces proliferationof Tregs in the mouse15 and human.4 TNFR2‐expressing Tregs are highly

selective destruction of autoreactive T cells and induction of Tregs thatsuppress cytotoxic T cells.

suppressive and appear to be the most suppressive Tregs identified todate in the mouse and human.16-19 Agonism of TNFR2 through use ofagonistic antibodies or transmembrane TNF induces IL2R (CD25), TNF,

1.4|

TNF induction with the BCG vaccine

and TRAF2 expression, all of which are elements of the TNFR2 signalling

In the past decade, interest in the nearly century‐old tuberculosis vac-

pathway for Treg expansion.4 Interestingly, the Tregs observed aftercine, BCG, has been revived for potential therapeutic uses in new indi-

expansion through TNFR2 agonism in a study by Okubo et al are acations, including type 1 diabetes and other forms of autoimmunity.

homogenous population, contrasting to the heterogeneous population

BCG has an excellent longstanding record of safety and tolerability.

observed when a TNFR1 agonist is used to trigger expansion in human

The most common adverse event, which is still rare, is suppurativecell cultures.4 This homogeneity is important, because heterogeneous

lymphadenitis, which is self‐limiting and does not require treatment.

progeny are capable of releasing pro‐inflammatory cytokines and also

The BCG vaccine's main appeal for investigations in the treatment of

can include cell populations with antagonistic properties. Further, theautoimmunity is its ability to induce TNF. BCG contains the avirulent

Tregs in the same study exerted an immunosuppressive function thattuberculosis strain Mycobacterium bovis and was first introduced into

may be beneficial in type 1 diabetes.

humans in 1921 as a vaccine to prevent tuberculosis. Since BCG's intro-

On an historical note, it is important to point out that the triggering

duction, an estimated 3 billion people worldwide have received theof TNF release by the host immune system after BCG vaccination or

BCG vaccine. However, because of declining incidence of tuberculosis

tuberculosis exposure defines the innate immune response. The ability

in Europe and the US, routine BCG vaccination has been discontinuedof BCG or other select microbial pathogens to trigger systemic

at these sites. By contrast, the BCG vaccine is broadly and uniformly“cachectin” release is well documented.20 After the cloning of cachectin,

administered in developing countries.

it was renamed TNF. Although many immune cells can produce andIn type 1 diabetes, the potential benefit of BCG vaccinations inrelease TNF after BCG exposures, macrophages, in general, release theestablished type 1 diabetes was first demonstrated in the NOD rodent

largest amount of this cytokine after exposure to this infection.

model. As previously discussed, TNF induction with CFA or BCG in the
NOD mouse reversed advanced disease by killing disease‐causing

1.3 | TNF induction and TNFR2 agonism as atreatment for type 1 diabetes, lessons from NOD mice

autoimmune cells and restoring insulin secretion.11,26 CFA and BCG
are similar products in that they contain Mycobacteria: CFA contains
inactivated Mycobacterium and BCG contains avirulent Mycobacterium

Historical evidence supports the premise that autoimmune‐pronethat has historically undergone many rounds of in vitro selection to

NOD mice with both type 1 diabetes and Sjögren's syndrome aredecrease virulence in humans. CFA is a research tool, whereas BCG

amenable to treatments with adjuvants that stimulate TNF, such as

is a clinical product manufactured according to Current Good

4 of 6

FAUSTMAN

Manufacturing Practices (CGMPs) monitored by the US Food and Drug
Administration. It is therefore suitable for use in the human.

Long‐term follow‐up of Phase I participants continues, including
analysis of patients in the placebo arm who have now received BCG

Recent human clinical trials in type 1 diabetes and multiple

in an open‐label crossover portion of the study. A randomized,sclerosis in adults who were administered the BCG vaccine show

placebo‐controlled Phase II trial is also currently underway, in which

therapeutic promise even after disease onset or in long establishedsubjects will be followed for 5 years. The Phase II trial has enrolled

autoimmunity,14,31-34 although early trials, conducted without an

type 1 diabetic subjects with long standing diabetes who demonstrateawareness of strains nor necessary dosing, showed variable effects. In

some small amounts of remaining C peptide as measured with anan early, uncontrolled trial of 17 patients who were newly diagnosed

ultrasensitive assay. The endpoint of this trial is a >10% lowering ofwith type 1 diabetes, a single‐dose of BCG led to a temporary

HbA1c values. Data from multiple sclerosis trials show that clinically

35

However, subsequent controlled

significant immune alterations after BCG administration may take timeclinical trials using a single low‐dose of BCG as the TICE strain andto occur.31 Therefore, a trial duration of 5 years has been selected for

36-38

epidemiologic studies in children with new onset type 1 diabetes

the Phase II type 1 diabetes study, as a clinical outcome, not just a

did not show a benefit to BCG vaccination. The reason for the negative

biomarker outcome, is desired.

remission in 11 patients (65%).

findings may be due to insufficient (ie, single) dosing, as well as the use

The positive findings from the Phase I trial are consistent withof different BCG strains such as TICE, which even has low efficacy eventrials of BCG vaccination in multiple sclerosis, an autoimmune diseasein mouse studies. Interestingly, the first study by Shehadeh et al dosing

in which autoreactive T cells are also susceptible to TNF‐triggered cell

BCG in new onset type 1 diabetic subjects used an older BCG strain

death. In trials conducted in Italy, BCG vaccination was found tothat is known to induce strong host TNF responses.35 By contrast,

decrease multiple sclerosis disease activity and prevent progression

the later type 1 diabetes studies frequently used the TICE strain ofof brain lesions in patients with relapsing‐remitting multiple

BCG which has lower efficacy in terms of NF‐κB induction and TNF

sclerosis.32,33 These studies were followed by a double‐blind,production, as well as lower protective responses against tuberculo-

placebo‐controlled Phase II trial testing BCG vaccination in subjects

sis.39,40 With a more advanced understanding of the mechanism ofwith early symptoms of multiple sclerosis (ie, clinically isolated

action of BCG, it is now possible to pair biomarkers for early indications

syndromes [CIS]), but who had not yet been definitively diagnosedof efficacy in the clinical trials. BCG's mechanism of action was notwith advanced multiple sclerosis.31,34 A single dose of BCG was

known until approximately 10 years ago, and it was not appreciatedadministered to 33 subjects, while an additional 40 subjects received

that strain differences and longer follow‐up of subjects were essential.

the placebo. Vaccinated subjects were significantly less likely to

About a decade after the first study of BCG in humans with type 1

develop lesions within 6 months of vaccination, and the number ofdiabetes, a double‐blind, placebo‐controlled, Phase I trial of repeat BCG

T1‐hypointense lesions was lower in the BCG group at 6, 12, andvaccination was conducted in adults with longstanding type 1 diabetes

18 months. Further, at the end of 5 years, 58% of subjects who(mean duration of diabetes: 15.3 years) at a single center in North

received BCG did not progress to multiple sclerosis, compared with

America.14 Six type 1 diabetic subjects were randomly assigned to

30% of those who received the placebo. Overall, clinical benefits after

BCG or placebo (2 injections spaced 4 weeks apart) and were

BCG administration in new onset multiple sclerosis were durable andcompared with self, a healthy paired control (n = 6) or reference

even enhanced at 5 years31 There were no major adverse events,

subjects with (n = 57) or without (n = 16) type 1 diabetes, depending

and the frequency of all adverse events did not differ between treatedon the outcome measure, over a 20‐week period. Within several weeks,

and placebo groups. A Phase III clinical trial is now underway (Personal

repeat BCG vaccinations led to a large increase in dead insulin‐correspondence with G. Ristori, Rome, Italy).

autoreactive T cells entering into the circulation (ie, selectively eliminated insulin‐autoreactive T cells) and transiently induced beneficial
Tregs for 4 to 6 weeks after vaccination. In these human studies, the1.5|

TNFR2 agonism in type 1 diabetes

Connaught strain of BCG (manufactured by Sanofi) was utilized. These

Unlike TNF induction through the BCG vaccine, which is currently

findings were not only seen in the BCG‐treated patients, but also in 1

advancing in human clinical trials, TNFR2 agonism as a treatment forplacebo‐treated patient who developed an acute infection with thetype 1 diabetes is still in the preclinical stage, although diverse studies

Epstein‐Barr virus (EBV) after enrollment. EBV infection is known toin various autoimmune settings are showing benefit. As mentioned

trigger robust release of TNF. Therefore, the response of the partici-

earlier, a TNFR2 agonist has been demonstrated to selectively killpant who unexpectedly developed EBV underscores the benefits ofautoreactive T cells from patients with type 1 diabetes in culture.5

20

triggering innate immunity

41

in longstanding type 1 diabetes.

Further in vitro studies show that a Treg activation defect in type 1

In 2 BCG‐treated subjects and the 1 EBV‐infected subject,diabetes can be corrected with TNFR2 agonism.42 Activated Tregs

treatment transiently restored a small amount of insulin production(aTregs) prevent or halt various forms of autoimmunity. Okubo et al

as measured by C‐peptide levels, as detected by an ultrasensitive

have shown that type 1 diabetics have elevated numbers of resting

assay. As expected from the long safety history of the BCG vaccine,Tregs (rTregs, CD4(+)CD25(+)Foxp3(+)CD45RA) and a decrease in

no major adverse events were reported. This trial was the first to

aTregs (CD4(+)CD25(+)Foxp3(+)CD45RO) compared with controls

demonstrate that, by transiently arresting the autoimmune response(n = 55 type 1 diabetics, n = 45 controls, P = 0.01), associated with athat underlies type 1 diabetes, BCG treatment or EBV infection cantrend for less residual C‐peptide secretion from the pancreas

pave the way for some degree of C‐peptide restoration, even after in(P = 0.08) and poorer HbA1C control (P = 0.03). TNFR2 agonism waspatients with a long duration since type 1 diabetes diagnosis.

used as a method for stimulating conversion of rTregs to aTregs, which

5 of 6

FAUSTMAN

corrected the activation defect. Further, TNFR2 agonism was superior

ETHICS STATEMENT

to standard protocols and to TNF in proliferating Tregs. The TNFR2
agonist‐expanded

functionallyThis is a review article that cites the peer‐reviewed papers of ourpotent by virtue of suppressing autologous cytotoxic T cells in a

Tregs

were

homogeneousandgroup and other groups. Therefore, the study designs are detailed indose‐dependent manner comparable to controls. Thus, targeting thethe primary papers, and this review does not include a study design

TNFR2 receptor for Treg expansion in vitro demonstrates a means towith the direct ethical statements of the human study or animal study

correct the activation defect in type 1 diabetes.43

designs. For our own published studies cited in this paper, all animal

Often when the benefit of TNF induction through BCG is

studies go through the office of human studies or the animal studies

described, it has been hard to reconcile with the vast autoimmune

offices to confirm the ethical treatment of humans and animals in

literature that shows some subsets of autoimmune subjects benefit

research.

from anti‐TNF therapy, such as subjects with rheumatoid arthritis
who benefit from anti‐TNF antibody therapies. Previously, it was

ORCID

presumed that anti‐TNF therapies “took away” TNF as their

Denise L. Faustman

http://orcid.org/0000-0002-0871-4812

mechanism for clinical benefit. It is worth mentioning that new data
perhaps explains this paradox. It is known from the rheumatoid

RE FE RE NC ES

arthritis literature that anti‐TNF therapies in the form of Remicade

1. Miyara M, Gorochov G, Ehrenstein M, Musset L, Sakaguchi S, Amoura
Z. Human FoxP3+ regulatory T cells in systemic autoimmune diseases.
Autoimmun Rev. 2011;10:744‐755.

and Adalimumab induce Tregs in autoimmune patients. These drugs
are antibodies that bind TNF. Another approved drug for rheumatoid
arthritis is Etancercept, a soluble TNFR2 antibody‐receptor linked
44

antibody; Etancercept does not induce Tregs in vivo.
18,45-48

humanTregs expand with TNF are potent Tregs.

In culture,

It is now appre-

ciated that the therapeutic anti‐TNF antibody Adalimumab inducesin vivo Tregs but by binding preferentially to membrane surface TNF
with trimerization that induces TNFR2 on Treg cells, both in vivo andin vitro.49 Because TNFR2 Tregs are the most suppressive Tregs known
to exist naturally as well as the abundant Treg subtype in cancer conferring suppression, this means anti‐TNF therapy is not working throughTNF reduction, but instead through TNF trimerization and TNFR2
induction of potent Tregs. Thus, adalimumab is expanding functional
and potent TNFR2 Tregs well with potent suppressive activity.49
Recent data show that TNFR2 restricts the pathogenicity of CD8
T cells in murine colitis.50 Additionally, a TNFR2 agonist expandsin vitro potent host Treg cells and in vivo also protects from acute graft
versus host disease in a mouse.43 In the human, exogenous TNFR2
activation protects from acute graft‐versus‐host disease (GVHD) via
host Treg cell expansion.51

2|

C O N CL U S I O N S

Administration of TNF inducers or TNFR2 agonists may represent a
new treatment strategy for type 1 diabetes. TNF induction and TNFR2
agonism have been associated with selective death of autoreactive T
cells in type 1 diabetes, induction of Tregs, and even early clinical signsof restoration of pancreatic islet function in vivo. In current type 1
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DLF is an employee of Harvard Medical School and Massachusetts
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companies for the advancement of the BCG clinical trials which are
wholly supported by philanthropy.

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How to cite this article: Faustman DL. TNF, TNF inducers,
and TNFR2 agonists: A new path to type 1 diabetes treatment.
Diabetes Metab Res Rev. 2017;e2941. https://doi.org/10.1002/
dmrr.2941