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*
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Immune Cell Biology Program, Naval Medical Research Institute, Bethesda, MD 20889; and
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production. Finally, Ab blockade of T cell CD28
during the first disease episode resulted in significant attenuation of
the subsequent disease course, with no significant relapses. In
contrast to previous studies targeting APC B7 with CTLA4-Ig, reagents
targeting CD28 can block ongoing disease. Therefore, the present
results suggest a clinically relevant therapeutic scenario for human
diseases, such as multiple sclerosis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although several different T cell-APC interactions can provide costimulation, the major costimulatory signal appears to be through the CD28 receptor on the T cell (4, 5, 6). The CD28 gene has been disrupted to create a mouse genetically deficient in CD28 (5). Studies using this mouse have demonstrated that some immune responses are dependent on CD28 costimulation (5, 7). However, other immune responses remain either partially or completely intact, suggesting less dependence on costimulation or the significance of other costimulatory pathways, such as the recently described inducible costimulator (5, 8, 9).
CTLA-4 (CD152) is also involved in the delivery of a secondary signal
that regulates T cell activation. Recent evidence suggests that T cell
activation is regulated by competing signals delivered by CD28 and
CTLA-4 (10, 11, 12, 13). Blockade of CTLA-4 with specific mAb can
exacerbate clinical signs of experimental autoimmune encephalomyelitis
(EAE)3 (14, 15). Anti-CTLA-4 injection at the onset of clinical signs
resulted in increased production of the proinflammatory cytokines IL-2,
IFN-
, and TNF- and increased clinical disease severity and
mortality (14).
The B7 molecules on the APCs, B7-1 (CD80) and B7-2 (CD86), are the counterreceptors for both T cell CD28 and T cell CTLA-4 (16, 17, 18, 19). Although it has been shown that either CD28 or CTLA-4 can bind to both B7-1 and B7-2, increasing evidence suggests that B7-1 and B7-2 may have distinct costimulatory functions (20, 21, 22, 23).
We have previously used the soluble receptor CTLA4-Ig to demonstrate a central role for B7-mediated costimulation in EAE induced by active immunization with myelin basic protein (MBP) (21, 24) and by adoptive transfer of MBP-specific lymph node cells (LNC) (21, 25). Those studies demonstrated that B7-mediated costimulation plays an important role during initial immune cell interactions, enhancing proliferation and cytokine production and determining encephalitogenicity. Those studies also demonstrated that the effects of CTLA4-Ig were schedule dependent. CTLA4-Ig administration can result in either suppression or enhancement of clinical disease in at least one active model of EAE (21).
The roles of the individual B7 molecules, B7-1 and B7-2, during the
initiation of EAE have been investigated by us (21, 24)
and others (23, 26). It appears that the effects of
anti-B7-1 and anti-B7-2 reagents in vitro and in vivo depend on
the model of EAE studied. However, it is clear that anti-B7-1
treatment ameliorates subsequent disease development, whereas
anti-B7-2 treatment usually exacerbates disease. Treatment with
both anti-B7-1 and anti-B7-2 may either ameliorate or
exacerbate disease, depending on how EAE is induced (21, 24). The mechanism of differential regulation of EAE by the
B7 molecules involves differential regulation of cytokines. Kuchroo et
al. have attributed the effects of repeated injections of Ab to
differential regulation of Th1/Th2 differentiation (23).
The effects of a single injection of Abs directed against B7-1 and B7-2
involve regulation of the encephalitogenic cytokine TNF-
(24). Blockade of B7-1 using Fab fragments during ongoing
EAE prevents epitope spreading and subsequent relapse
(26), whereas using the intact mAb exacerbates disease
(27).
Given the complexity of B7:CD28/CTLA-4 interactions, B7-mediated
costimulation is not necessarily equivalent to CD28-mediated
costimulation. Indeed, previous studies predict that CTLA4-Ig therapy
could prevent B7:CTLA-4 interaction and result in enhanced disease
(21). Therefore, direct manipulation of CD28 and CTLA-4
may be preferable to B7 blockade. We have therefore begun to directly
target CD28 with mAb Fab fragment in the EAE model. CD28 blockade
either during disease induction or after the establishment of clinical
disease resulted in disease amelioration. This amelioration was
associated with suppressed production of the proencephalitogenic
cytokine TNF- and decreased production of IL-2. Therefore, direct
targeting of T cell CD28 is a potential strategy for treatment of
autoimmune demyelinating disease.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female (PL x SJL)F1 mice were
obtained from The Jackson Laboratory (Bar Harbor, ME). All (PL x
SJL)F1 mice were 10 to 12 weeks of age when
experiments were initiated. Transgenic mice bearing the V
8.2,
V2.3 TCR specific for MBP Ac1–11 on the B10.PL background were
provided by Dr. Joan Goverman (University of Washington, Seattle, WA).
These mice were bred and maintained in our animal colony in compliance
with the Animal Studies Committee (28, 29). In conducting
this research, the investigators adhered to the Guide for
Laboratory Animal Facilities and Care as promulgated by the
Committee on the Guide for Laboratory Animal Resources
(National Academy of Sciences, National Research Council, Department of
Health and Human Services, Publication No. (NIH) 86-23).
Reagents
Whole MBP was prepared from guinea pig spinal cords (Rockland, Gilbertsville, PA) as previously described (30). Hamster anti-mouse CD28 hybridoma 37–51 was kindly provided by Dr. James P. Allison (University of California, Berkeley) (31), and mAb was purified from tissue culture supernatant. Hamster anti-mouse CD28 mAb PV-1 (32) was purified from tissue culture supernatant also. Control hamster IgG was purchased from Rockland. The endotoxin content of the Abs used in these studies was <0.4 EU/mg. Fab fragments were made using the ImmunoPure Fab Kit (Pierce, Rockford, IL) according to the manufacturer’s instructions. The Fab fragments were subsequently run on a 12% SDS-PAGE gel under nonreducing conditions with m.w. markers and whole Abs. Gels were stained with Coomassie blue, and purity was assessed.
Induction of EAE
For actively induced EAE, mice were immunized by s.c. injection of 400 µg MBP emulsified in CFA (Difco Laboratories, Detroit, MI) above the shoulders and flanks and i.p. injection of 100 ng pertussis toxin (List Biological Laboratories, Campbell, CA) on days 0 and 2. Animals were examined daily for signs of disease and graded as previously described (33): 0, no abnormality; 1, flaccid tail; 2, moderate hind limb weakness; 3, severe hind limb weakness; 4, complete hind limb weakness; and 5, quadriplegia or premoribund state.
For adoptively transferred EAE, mice were immunized with MBP (400 µg) in CFA, and 10 days later draining lymph nodes were removed. MBP-specific LNC (4 x 106) were cultured in 2 ml of RPMI 1640 (BioWhittaker, Walkersville, MD) supplemented with 10% FBS, penicillin G (100 U/ml), glutamine (2 mM), nonessential amino acids, HEPES buffer, 2-ME (5 x 10-5 M), and MBP (25 µg/ml) for 3 days in 24-well plates (Costar, Corning, NY). LNC were washed and adjusted to the required concentration in PBS so that each recipient received 3 x 107 cells in a 0.2-ml suspension via the tail vein. Recipient mice were observed daily for signs of disease, as above.
For adoptively transferred EAE using transgenic T cells with a TCR specific for MBP1–11, splenocytes from transgenic mice were cultured 1:5 with wild-type splenocytes from B10.PL mice at a final concentration of 4 x 106 cells/ml in medium as described above with MBP (25 µg/ml) for 48 h. After 48 h, T cells were washed and adjusted to the required concentration so that each naïve B10.PL recipient received 2 x 107 cells in a 0.2-ml suspension i.p. Recipient mice were observed daily for clinical signs of disease as above.
ELISA.
TNF- was assayed with the Endogen (Cambridge, MA) ELISA kit
according to the manufacturer’s instructions.
Measurement of IL-2 production
An IL-2-dependent cell line, CTLL.EV (34), was generously provided by Dr. W. Paul (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD). Supernatants (50 µl) from experimental cell cultures were assayed in quadruplicate. Results were compared, with proliferation of the cell line to known amounts of IL-2 as standards. SD of replicate cultures was <10% of the mean (21, 25).
Statistics
Treatment effects were assessed with the Mann-Whitney sum of
ranks test. Differences in disease incidence were analyzed using
Fisher’s exact test. Differences in TNF- release by ELISA were
analyzed with the Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously shown that in vitro blockade of B7 reduces the
ability of MBP-primed cells to transfer EAE (21, 25). In
addition to its negative effects on T cell activation, CTLA-4 can also
provide costimulation for some T cell responses (35, 36, 37).
Previous experiments with injection of anti-CD28 Abs have shown
effects that are consistent with induction of both agonistic and
antagonistic effects (38). Therefore, we used
anti-CD28 Fab (mAb PV-1) to specifically block B7:CD28 interaction
during EAE, as anti-CD28 Fab fragments do not induce signal
transduction and yet remain capable of efficient blockade of B7
binding. Mice were immunized with MBP (400 µg) in CFA, and 10 days
later draining lymph nodes were removed and cultured in the presence or
absence of CD28 blockade. As shown in Fig. 1
, in vitro activation of MBP-primed
cells in the presence of anti-CD28 Fab fragments resulted in both
lower disease incidence and decreased disease severity in animals
developing clinical disease. In addition, the presence of anti-CD28
Fab resulted in a dramatic reduction in IL-2 production (Fig. 2), consistent with the known role of the
B7-CD28 pathway in the production of this cytokine (39).
These results demonstrate in the adoptive transfer model of EAE that
encephalitogenic T cells require a costimulatory signal, delivered
through CD28, to mediate significant disease-producing capability and
secretion of inflammatory cytokines.
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The effect of anti-CD28 Fab injection lasted for the duration of
the observation period (73 days). Thus, in the active model of EAE, a
transient interruption of CD28 function results in long-term
amelioration of clinical disease activity.
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The above results suggested that the likely mechanism of
inhibition of disease was that encephalitogenic
CD4+ precursors failed to produce adequate IL-2
and expand sufficiently during CD28 blockade to reach the threshold
necessary to cause disease. To address whether the effect of
anti-CD28 merely reflected an inhibition of expansion of
encephalitogenic precursors, MBP-specific TCR transgenic T cells were
cultured at a very high precursor frequency in vitro with MBP and
anti-CD28 blockade. Under these conditions, significant differences
in the ability to induce EAE were not noted (Table I). In addition, no differences in IL-2,
IL-4, or IFN- production in tissue culture supernatants were noted
at 24 or 48 h after initiation of culture of these cells with Ag.
(Fig. 4 and data not shown). These
results, plus the ability of anti-CD28 to have such a long-lasting
effect during Ag priming, strongly suggest that the effect mediated by
anti-CD28 Fab in this model is due to inhibition of expansion of
CD4+ encephalitogenic precursors that
mediate EAE.
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Most studies of B7-mediated costimulation have focused on the
initial immune cell interactions during Ag priming. While
administration of anti-B7-1 Fab fragment can suppress established
EAE (26), CTLA4-Ig injection does not alter established
disease (25, 40). We therefore evaluated the ability of
specific CD28 blockade to suppress EAE in the direct model after
completion of initial Ag priming. As shown in Table II, anti-CD28 Fab injection just
before disease onset can ameliorate disease.
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, we delayed injection of
anti-CD28 Fab or control hamster Fab until after the first mice
displayed clinical signs. Animals then received 10 µg of
anti-CD28 Fab or control hamster Fab every other day for 14 days
beginning the day after the first animal displayed clinical disease
signs. In this experiment, none of the anti-CD28 Fab recipients
developed disease for 21 days. After the initial 21 days, the severity
of disease eventually developed by the anti-CD28 Fab recipients was
less severe than that developed by the control mice. These results
demonstrate that blockade of B7:CD28 interactions just before the onset
of disease can inhibit clinical signs of EAE. These results were
surprising in that previous studies have shown that effector cells are
relatively independent of costimulation.
We next assessed the effect of CD28 on the production of TNF-, an
important proinflammatory mediator of autoimmune demyelination
(41). Animals were injected i.p. with 10 µg of
anti-CD28 Fab or control hamster Fab every other day for 14 days
beginning the day after the first animal displayed clinical disease
signs. LNC were obtained 7 days after the final injection and were
cultured in the presence or absence of MBP. TNF- release into
culture supernatants was assessed by ELISA. As shown in Fig. 5, CD28 blockade significantly reduced
TNF- secretion.
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Finally, we asked whether CD28 blockade, after the establishment of clinical disease, could attenuate the course of clinical EAE. We immunized (PL x SJL)F1 mice and allowed them to develop EAE. After all of the mice had signs of EAE for at least 2 consecutive days, they were divided into two groups and injected with 10 µg of either anti-CD28 mAb 37–51 or control hamster IgG every other day. The mean maximal score achieved by both groups of mice before injection was 2.8. Each animal received six injections between days 20 and 30 postimmunization.
As shown in Fig. 6, anti-CD28
injection resulted in an attenuated disease course. The control group
of animals had two episodes of relapsing disease, whereas the mice
given CD28 blockade did not develop disease exacerbations. The
therapeutic effect of CD28 blockade continued after the last injection
until the end of the observation period on day 46 postimmunization.
These results suggest that direct blockade of T cell CD28 represents a
potential therapeutic approach for ongoing autoimmune
demyelination.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The interactions involving B7-1 and B7-2 with either CD28 or CTLA-4 during EAE and other autoimmune disorders, such as diabetes, are complex. Accessory signals delivered through the B7 receptors can either provoke or prevent clinical EAE (14, 21, 24, 25, 26). Injection of anti-B7-1 Ab suppresses the induction of EAE (24), and anti-B7-2 injection exacerbates clinical disease (21, 23, 24). Conversely, in the NOD mouse model of autoimmune diabetes, anti-B7-2 administration was protective and anti-B7-1 administration exacerbated disease (20). Therefore, the contribution of the individual B7 molecules is dependent on the disease model as well as on the timing of administration of the various reagents.
Studies in which B7-1 and B7-2 are blocked simultaneously suggest further complications to approaches that target both B7-1 and B7-2. Injection of both anti-B7-1 and anti-B7-2 can either ameliorate (21) or exacerbate EAE (24), depending on the immunization protocol used for inducing EAE. In one model of EAE, CTLA4-Ig, which binds to both B7-1 and B7-2, can either suppress or enhance clinical disease, depending on the injection protocol used (21).
Therefore, it appears that blockade of the B7 ligands during periods when CTLA-4 regulatory interactions may predominate exacerbates autoimmunity. Although the dynamics of B7:CD28 and B7:CTLA-4 interactions might be defined in murine models of EAE, they may be more difficult to predict in patients undergoing less defined disease courses. Therefore, directly targeting CD28 costimulation represents an attractive alternative approach.
In the present studies, anti-CD28 Fab injection, either during Ag
priming or later, before disease onset, significantly ameliorated EAE.
This amelioration was associated with ablated TNF- production.
TNF- has been associated with encephalitogenicity (41, 44, 45). T cell infiltration into the CNS, together with TNF-
blockade, results in the inhibition of clinical signs of EAE
(45). On the other hand, recent studies have shown that
EAE can be induced in mice deficient in lymphotoxin- and
TNF-, suggesting that other cytokines can replace their central
pathogenic role in EAE (46).
Most importantly, CD28 blockade using a blocking mAb attenuated established EAE. Mice receiving intact anti-CD28 mAb 37–51 underwent attenuated clinical disease and did not undergo significant subsequent relapses. Disease attenuation was also evident after the cessation of treatment, suggesting that short-term CD28 blockade may be sufficient to control expansion or effector functions of autoreactive effector T cells and thereby ameliorate the autoimmune response.
The ability of CD28 blockade to ameliorate established EAE is consistent with the ability of B7-1 Fab to prevent epitope spreading and relapse (26). Conversely, CTLA4-Ig has not been effective at blocking ongoing EAE (25), even when using a homologous construct with the murine CTLA-4 extracellular domain (P. J. Perrin and C. H. June, unpublished observations). The present results, together with those of Miller et al. (26), suggest that CD28-targeted therapy may be a useful approach to autoimmune demyelinating diseases.
It is important to note that, although the encephalitogenic response is reduced, it is not completely eliminated, suggesting that encephalitogenic T cells, which may not be dependent on CD28, mediated costimulation. This observation would be consistent with recent findings in mice deficient in CD28. In an autoimmune myocarditis model, CD28-/- mice developed autoimmune heart disease, although it was less severe than that observed in heterozygous littermates (47). In addition, breeding NOD mice to CD28-/- exacerbated autoimmunity, suggesting that CD28 plays an important regulatory role in that disease model (48). However, the ability to suppress the ongoing immune response suggests that preactivated T cells may be, at least partially, dependent on T cell costimulation. Alternatively, CD28 blockade may prevent the further recruitment and activation of naïve T cells and interfere with the process known as epitope spreading (26, 49).
Collectively, our studies and those of others using CD28 Fab or other
B7:CD28 antagonists in wild-type mice would suggest that the effect is
primarily mediated by inhibiting the expansion of MBP-reactive T cells
that mediate the effect resulting in clinical signs of disease
(21, 24, 25, 26). However, it is interesting that when the
encephalitogenic T cells are cultured at a very high precursor
frequency in vitro, as was the case when we used the MBP-specific TCR
transgenic T cells, the anti-CD28 blockade was ineffective in
blocking EAE or IL-2 production (Table I and Fig. 4). It is possible
that at high Ag-specific T cell precursor frequency, inability to block
all B7:CD28 interactions results in IL-2 production, which then
overcomes the result of the blockade, which is otherwise effective when
the Ag-specific cells are at a low precursor frequency, as may be the
case in wild-type mice. In addition, it is possible that B7 expression
on the activated T cells themselves, particularly at high T cell
precursor frequency, may be able to provide an additional costimulatory
signal. However, B7 expression on T cells may also regulate the immune
response in the setting of a high density of responder T cells. The
presence of anti-B7-1 and anti-B7-2 Abs augments T lymphocyte
proliferation in the presence of optimal stimulation by anti-CD28
Abs, suggesting that B7:CTLA-4 interactions may mediate inhibitory
signals (50).
Although the data presented in this article suggest that the major effect of CD28 blockade is to reduce the expansion of encephalitogenic precursors, recent data published by our group suggest the possibility that CD28 blockade can produce qualitative effects on the ability to induce inflammation in the CNS. Although CD28+/+ C57BL/6 mice develop EAE in response to myelin/oligodendrocyte glycoprotein immunization, CD28-/- mice develop experimental autoimmune meningitis (51). Experimental autoimmune meningitis is characterized by a polymorphonuclear neutrophil-dominated inflammatory response within the leptomeninges in the absence of classical perivascular infiltrates in the CNS characteristic of EAE. Thus, CD28 signaling may be important for T cells to be able to enter the CNS and induce encephalomyelitis, rather than merely meningitis. However, the present study demonstrates that interruption of the costimulatory signal delivered to encephalitogenic T cells through CD28 can result in inhibition of their expansion and important long-term clinical effects in an organ-specific model of autoimmunity.
Ag-specific tolerance is a goal for the treatment of autoimmune diseases. This could be accomplished by preventing the costimulatory signal, without interfering with presentation of Ag to the TCR. Furthermore, because activated cells are targeted with this strategy, the autoantigen does not need to be defined. This is particularly important when considering treatments for diseases such as multiple sclerosis, in which an immune-mediated process is very likely but the identity of the autoantigen unknown (52).
In conclusion, previous studies have examined the complex and varying roles of B7-mediated costimulation using reagents specific for the B7 molecules and/or CTLA-4. CTLA4-Ig or B7 Abs could potentially interfere with B7:CTLA-4 interactions that are important for regulation of an immune response. Regulation of the CD28 signal represents a more direct approach to targeting the T cells that mediate EAE than does manipulation of B7. These studies establish the feasibility of this strategy.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Peter J. Perrin, Department of Medicine, Pulmonary, Allergy, and Critical Care Section, 909 BRB II, 421 Curie Boulevard, Philadelphia, PA 19104-6160. E-mail address:
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; LNC, lymph node cells.
Received for publication December 23, 1998. Accepted for publication May 24, 1999.
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8.2-specific T-cell lines from TCR V 8.2 transgenic mice utilize the same V and V genes: specificity associated with the V CDR3-J region. J. Neurosci. Res. 47:489.[Medline]
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and lymphotoxin are not required for induction of acute experimental autoimmune encephalomyelitis. J. Exp. Med. 185:2177. secreting T cells precedes recovery from acute monophasic experimental autoimmune encephalomyelitis. J. Autoimmun. 9:587.[Medline]This article has been cited by other articles:
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
3) were
cultured in the presence of medium or MBP. TNF-