Costimulation and autoimmunity

Current Opinion in Immunology

Volumn 8, Issue 6, 1996, Pages 822-830

  Tivol, Elizabeth A ^a   Schweitzert, A Nicola ^b   Sharpe, Arlene H ^b  

^a BLOOD RESEARCH INSTITUTE   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOTOXIC T LYMPHOCYTE ANTIGEN 4;

AUTOIMMUNITY; DISEASE COURSE; ETIOLOGY; IMMUNOLOGICAL TOLERANCE; IMMUNOSTIMULATION; REVIEW; T LYMPHOCYTE ACTIVATION;

EID: 0030459799     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(96)80011-2     Document Type: Article

References (66)

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6. Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Gray GS, Nadler LM: CTLA-4 mediated costimulation induces apoptosis of activated human T lymphocytes. Proc Natl Acad Sci USA 1994, 92:811-815.
7. Krummel M, Allison J: CD2B and CTLA-4 have opposing effects on the response of T celts to stimulation. J Exp Med 1995, 182:459-466. Similar to [5,6], this study also suggests that CTLA-4 delivers an inhibitory signal to the T cell. T cells did not proliferate when stimulated with an antiCTLA-4 mAb and a suboptimal concentration of anti-CD3. In contrast, blocking CTLA-4 engagement with soluble anti-CTLA-4 mAbs enhanced the proliferation of T cells stimulated with anti-CD3 and anti-CD28 In the presence of cross-linking antibodies, however, anti-CTLA-4 inhibited proliferation of T cells and IL-2 production by T cells incubated with anti-CD3 and anti-CD28.
8. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bljestone JA, Sharpe AH: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995. 3:541-547. This paper describes the phenotype of CTLA-4-deficient mice, which revealed a critical role for CTLA-4 in downregulating T cell activation. The mice suffered lymphadenopathy and splenomegaly, developed particularly severe myocarditis and pancreatitis, and died at 3-4 weeks of age, The T cells of these mice proliferated spontaneously in vitro and produced abundant cytokines See also [9**].
9. -/- T cells remain sensitive to cell death induced by either cross-linking of the FasR or gamma irradiation.
10. Linsley PS, Golstein P: Lymphocyte activation: T cell regulation . by CTLA-4. Gun Biol 1996, 4:398-400. This is a concise, thoughtful review comparing the functions of CTLA-4 and CD28.
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12. 2. Linsley PS, Greene JL, Brady W, Bayorath J, Ledbetter JA, Peach R: Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA4 receptors. Immunity 1994, 1:793-801.
13. Lenschow DJ, Sperling AI, Cooke MP, Freeman G, Rhee L, Decker DC, Gray G, Nadler LM, Goodnow CC, Bluestone JA: Differential up-regulation of the B7-1 and B7-2 costimulatory molecules following immunoglobulin receptor engagement by antigen. J Immunol 1994, 153:1990-1997.
14. Freeman GJ, Boussiotis VA, Anumanthan A, Bernstein GM, Ke X-Y, Rennert PD, Gray GS, Gribben JG, Nadler LM: B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 1995, 2:523-532. These studies compared the function of B7-1 and B7-2 in vitro using Chinese hamster ovary cell transfectants expressing either human B7-1 or B7-2. These transtactants equivalently costimulated human CD4+ T cells to produce IL-2 and interferon-γ. B7-2 transfectants induced significantly more IL-4 production than B7-1, however, with the greatest difference seen in naive T cells. These studies suggest a preferential role for B7-2 in Th2 Subset differentiation.
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20. + T cells from CTLA-4-lg transgenic mice were not anergic and remained responsive to superantigen in vitro. Therefore, CTLA-4-lg was found to prevent, rather than facilitate, tolerance induction in CD4+ T cells. This study suggests that signaling via a B7-dependent mechanism is needed to induce tolerance.
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22. Van Parijs L, Abbas AK: Role of Fas-mediated cell death in the regulation of immune responses. Curr Opin Immunol 1996, 8:355-331. A recent thoughtful review of the role of the Fas-FasL pathway in salf-tolerance and autoimmunity. The recent advances in the biochemical mechanisms of Fas-mediated killing are summarized.
23. Leach DR, Krummel MF, Allison JP: Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996, 271:1734-1 736. This study demonstrates thai anti-CTLA-4 mAbs can accelerate the rejection of both B7-1 positive and B7-1 negative colon carcinoma cells, and can protect against subsequent carcinoma cell challenge. Anti-CTLA-4 treatment also reduced the growth of established tumors, suggesting that blocking the inhibitory effects of CTLA-4 can enhance antitumor immune responses at both early and later stages of tumor development.
24. Karandikar N, Vanderlugt CL, Walunas TL, Miller SD, Bluastone JA: CTLA-4: a negative regulator of autoimmune disease. J Exp Mad 1996, 134:783-788. This study explores the role of CTLA-4 in the development of EAE. Treatment of T cell clones specific for PLP139-151 with anti-CTLA-4 mAbs enhanced both their proliferation in vitro and their ability to induce disease in vivo. AntiCTLA-4 mAb treatment of recipients of adoptively-transferred activated PLPspecific T cells accelerated and exacerbated disease. Anti-CTLA-4 treatment of mice also exacerbated relapses in R-EAE. These observations suggest that CTLA-4 plays a significant role in the development of EAE. (See also [25-].)
25. Perrin R Maldonado J, Davis TA, June CH, Racke MK: CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis. J Immunol 1996, 157:1333-1336. Similar to [24*], this study shows that anti-CTLA-4 mAb treatment can exacerbate EAE. Treatment with anti-CTLA-4 after the onset of clinical symptoms increased disease severity and proinflammatory cytokine production,
26. Krummel MF, Allison JP: CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Btp Med 1996, 183:2533-2540. This study examines the events following CTLA-4 engagement in freshly isolated CD3+ T cells. Ligation of CTLA-4 inhibited proliferation and IL-2 production in cells stimulated with immobilized anti-CD3 and anti-CD28, but had no effect on viability or the induction of apoptosis. Inhibition of proliferation appears to be a consequence of arrest of cells in G.yG, stage of the cell cycle, possibly due to diminished IL-2 production. CTLA-4 engagement also inhibited the expression of IL-2R and CD69, indicating that CTLA-4 signaling inhibits an early stage of T cell activation. (See also 127'].)
27. Walunas TL, Bakker CY, Bljestone JA: CTLA-4 ligation blacks CD28-dependent T cell activation. J Exp Med 1993, 183:2541-2550. Similar to (26*), this study investigates the mechanism by which CTLA-4 blocks CO28-mediated activation of T cells. Incubation of activated CD3+ lymph node cells with anti-CTLA-4 antibodies inhibited proliferation, IL-2 production, IL-2R expression, and cell cycle progression, but did not induce apoptosis. The addition of exogenous IL-2 restored proliferation and IL-2R expression, suggesting that CTLA-4 signaling blocks CD28-mediated activation by inhibiting IL-2 production. It should be noted that the anti-CTLA-4 mAbs used in this study and in (26') could block B7-CTLA-4 interactions, in contrast to the mAbs used in [6], which bound to a distinct epitope and could induce apoptosis.
28. Marengere LEM, Waterhouse P, Duncan GO, Mittrucker H, Feng G, Mak TW: Regulation of T cell receptor signaling by tyrosine phosphatase syp association with CTLA-4. Science 1996, 272:1170-1173, This study shows that the Ras pathway and the TCR-specific kinases Fyn, Lck, and ZAP-70 are hyperactivated in CTLA-4- T cells. Targets of tyrosine phosphorylation after TOR activation, including CDSt, and p52Sh(: were hyperphosphorylated in CTLA-4- T cells. An association of CTLA-4 with the tyrosine phosphatase, SYP, was demonstrated, suggesting that CTLA-4 regulates CD28-mediated activation of tyrosine kinases through SYP.
29. Doody GM, Justement LB, Delibrias CC, Matthews RJ, Lin J, Thomas ML, Fearon DT: A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP. Science 1995, 269:242-244.
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32. Burshtyn DM, Scharenberg AM, Wagtmann M, Rajagopalan S, Berrada K, Yi T, Kinet JP, Long EO: Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity 1996, 4:77-85.
33. Harlan DM, Abe R, Lee KP, June CH: Potential roles of the B7 and CD28 receptor families in autoimmunity and immune evasion. Clin Immunol Imrnuncpathol 1995, 75:99-111. This is a thoughtful analytical review of the B7-CD28/CTLA-4 pathway, which emphasizes the clinical potential of manipulating this pathway for immunosuppression or immunostimulation.
34. Cross AH, Girard TJ, Giacoletto KS, Evans RJ, Keeling RM, Lin RF, Trotter JL, Karr RW: Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA4-Fc supports a key role lor CD2B (stimulation. 1 Clin Invest 1995, 95:2783-2789. This study shows that CTLA-4-Ig can prevent the induction of EAE and lead to effective long-term suppression of EAE, even altar the cessation of treatment. T cells from these mica could still proliferate in response to PLP in vitro and could transfer EAE upon adoptive transfer, however, suggesting that CTLA-4-lg treatment did not induce T cell tolerance to antigen. This study demonstrates an important role for B7-CD28/CTLA-4 interactions in the pathogenesis of EAE and suggests the clinical potential for this therapeutic approach for MS.
35. Racke MK, Scott DE, Quigley L, Gray GS, Abe R, June CH, Perrin PJ: Distinct roles for B7-1 (CD80) and B7-2 (CD86) in the initiation of experimental allergic encephalomyelitis. J Clin Invest 1995, 96:2195-2203. This study examines the effects of manipulation of the B7-CD29/CTLA-4 pathway in the active and passive transfer models of EAE. In actively induced EAE, a single injection of anti-B7-1 could significantly reduce disease, whereas anti-B7-2 exacerbated disease. A single injection of CTLA-4-lg two days after immunization could suppress disease, whereas multiple injections ol CTLA-4-lg (from day -1 to day 1 7) could enhance disease. In adoptively transferred EAE, in vitro activation of MBP-specific T cells could be markedly inhibited by anti-87-1 plus anti-B7-2, but by neither mAb individually. This in vitro treatment with anti-B7-1 and B7-2 led to a delay in the onset and a reduction in the severity of clinical disease upon the adoptive transfer of the treated MBP-specific T cells. This study illustrates the potential promise, as well as the difficulties, in manipulating this pathway lor therapeutic benefits. The timing of treatment appears critical, and may be related to the distinct temporal expression of the receptors and ligands in the pathway and their complex interactions, which can result in positive or negative signals for T cell activation.
36. Perrin PJ, Scott D, Quigley L, Albert PS, Feder O, Gray GS, Abe R, June CH, Racke MK: Role of B7/CD28 CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis. J Immunol 1995, 154:1481-1490. This study examines the effects of CTLA-4-lg administration at various times during chronic R-EAE induced by the transfer of MBP specific T cell lines. CTLA-4-lg treatment o( MBP-primed lymph node cells in vitro prior to transfer attenuated the induction of R-EAE. When CTLA-4-lg was administered to donor mice (from day -1 lo day 10) immunized with MBP and the primed cells were incubated with CTLA-4-lg prior to transfer, there was a marked Suppression of R-EAE. CTLA-4-lg treatment of recipients of activated MBPspecrfic T cells neither affected disease course nor severity, however. These data suggest that the B7-CD28/CTLA-4 pathway plays an important role in the development of encephalitogenic T cells and in the establishment of R-EAE.
37. Khoiiry SJ, Akalin E, Chandraker A, Turka LA, Linsley PS, Sayegh MH, Hancock WW. CD28-B7 costimulatory blockade by CTLA4lg prevents actively induced experimental autoimmune encephalomyelitis and inhibits Th1 but spare Th2 cytokines in the central nervous System. J Immunol 1995, 155:4521-4524. This study examines the effects of CTLA-4-lg on the course of EAE in the Lewis rat model. CTLA-4-lg administered from day 0 to day 10 significantly reduced the incidence, duration, and severity of EAE. When CTLA-4-lg treatment was begun on day 7 or day 10 after immunization when pathological disease was present, there was still a marked suppression of disease. The CTLA-4-lg protective effect could not be reversed by in vivo administration of IL-2. Immunohistological analyses of rats treated with CTLA-4-lg indicated thai CTLA-4-lg inhibited trie inflammatory Th1 response in the CNS, and upregulated protective Th2 cytokines, suggesting that CTLA-4-lg mediates protective effects by immune deviation. See also [38*].
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41. Kuchroo V, Prabhu Das M, Brown JA, Ranger AM, Zanwil SS, Sobel RA, Weiner HL, Nabavi N, Glimcher LH: B7-1 and B7-2 costimulatory molecules differentially activate the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995, 80:707-716. This study snows that anti-B7-1 mAbs administered at the time of immunization with PLP139-151 can reduce the incidence of acute EAE, whereas antiB7-2 mAbs increased disease severity. Anti-B7-1 mAbs did not inhibit the induction of PLP-specific T cells, but instead altered the cytokine profile of the responding cells, resulting in the predominant generation of Th2 clones, whose transfer both prevented induction of EAE and abrogated established disease. This study suggests that anti-B7-1 can block Thl activation and consequently the progression of EAE. The data show that manipulation of the B7-CD28/CTLA-4 pathway can skew the balance of the immune response by influencing the nature of the cytokines produced in response to antigen exposure.
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