Research Article
Distinct mechanisms of action of anti-CD154 in early versus late treatment of murine lupus nephritis
Sergio A. Quezada,
Maria Eckert, Oyedele A. Adeyi,
Alan R. Schned,
Randolph J. Noelle,
Christopher M. Burns,
Sergio A. Quezada
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorOyedele A. Adeyi
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorAlan R. Schned
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorRandolph J. Noelle
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorCorresponding Author
Christopher M. Burns
Dartmouth Medical School, Lebanon, New Hampshire
Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756Search for more papers by this authorSergio A. Quezada,
Maria Eckert, Oyedele A. Adeyi,
Alan R. Schned,
Randolph J. Noelle,
Christopher M. Burns,
Sergio A. Quezada
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorOyedele A. Adeyi
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorAlan R. Schned
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorRandolph J. Noelle
Dartmouth Medical School, Lebanon, New Hampshire
Search for more papers by this authorCorresponding Author
Christopher M. Burns
Dartmouth Medical School, Lebanon, New Hampshire
Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756Search for more papers by this authorAbstract
Objective
Treatment with anti-CD154 antibody is known to ameliorate murine lupus nephritis when given early in the disease. The aims of this study were to identify the mechanism of this early effect, to determine whether late anti-CD154 treatment could halt established nephritis, and, if so, to examine potential mechanisms of late efficacy.
Methods
We studied the effects of anti-CD154 treatment on autoantibody production and immune complex deposition, renal pathology, survival, and renal cytokine and chemokine messenger RNA (mRNA) expression both in (NZB × NZW)F1 mice (BW mice) and in NZM.2410 mice.
Results
Early treatment with anti-CD154 produced long-term survival in BW mice, with abrogation of renal immune complex deposition for months after treatment was stopped. Late anti-CD154 treatment, started after development of nephritis, could halt disease in ∼40% of mice. In some mice, proteinuria could be reversed repeatedly with sequential courses of anti-CD154 antibody. The remissions induced by late treatment with anti-CD154 occurred despite ongoing renal immune complex deposition. In preliminary studies, responding mice had rapid reductions in renal mRNA for transforming growth factor β, interleukin-10, and tumor necrosis factor α.
Conclusion
Amelioration of murine lupus by anti-CD154 therapy is mediated by distinct mechanisms in early versus late intervention. We postulate that anti-CD154 therapy prevents autoantibody production and renal immune complex deposition in the early, induction phase and limits secondary tissue damage in situ in the late, effector phase. These data demonstrate that CD40–CD154 interactions are critical for the maintenance of autoimmunity and suggest a potential role for anti-CD154 as a therapeutic agent in established human lupus.
REFERENCES
- 1 Boumpas DT, Austin HA III, Fessler BJ, Balow JE, Klippel JH, Lockshin MD. Systemic lupus erythematosus: emerging concepts. Part 1: Renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease. Ann Intern Med 1995; 122: 940–50.
- 2 Wofsy D, Ledbetter JA, Hendler PL, Seaman WE. Treatment of murine lupus with monoclonal anti-T cell antibody. J Immunol 1985; 134: 852–7.
- 3 Wofsy D, Seaman WE. Reversal of advanced murine lupus in NZB/NZW F1 mice by treatment with monoclonal antibody to L3T4. J Immunol 1987; 138: 3247–53.
- 4 Datta SK, Patel H, Berry D. Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis. J Exp Med 1987; 165: 1252–68.
- 5 Ando DG, Sercarz EE, Hahn BH. Mechanisms of T and B cell collaboration in the in vitro production of anti-DNA antibodies in the NZB/NZW F1 murine SLE model. J Immunol 1987; 138: 3185–90.
- 6 Sainis K, Datta SK. CD4+ T cell lines with selective patterns of autoreactivity as well as CD4- CD8- T helper cell lines augment the production of idiotypes shared by pathogenic anti-DNA autoantibodies in the NZB x SWR model of lupus nephritis. J Immunol 1988; 140: 2215–24.
- 7 Naiki M, Chiang BL, Cawley D, Ansari A, Rozzo SJ, Kotzin BL, et al. Generation and characterization of cloned T helper cell lines for anti-DNA responses in NZB.H-2bm12 mice. J Immunol 1992; 149: 4109–15.
- 8 Mohan C, Adams S, Stanik V, Datta SK. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 1993; 177: 1367–81.
- 9 Mamula MJ, Fatenejad S, Craft J. B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol 1994; 152: 1453–61.
- 10 Vogel LA, Noelle RJ. CD40 and its crucial role as a member of the TNFR family. Semin Immunol 1998; 10: 435–42.
- 11 Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, et al. Molecular and biological characterization of a murine ligand for CD40. Nature 1992; 357: 80–2.
- 12 Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A 1992; 89: 6550–4.
- 13 Gauchat JF, Aubry JP, Mazzei G, Life P, Jomotte T, Elson G, et al. Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production. FEBS Lett 1993; 315: 259–66.
- 14 Hermann P, Van KC, Gaillard C, Banchereau J, Blanchard D. CD40 ligand-positive CD8+ T cell clones allow B cell growth and differentiation. Eur J Immunol 1995; 25: 2972–7.
- 15 Horner AA, Jabara H, Ramesh N, Geha RS. gamma/delta T lymphocytes express CD40 ligand and induce isotype switching in B lymphocytes. J Exp Med 1995; 181: 1239–44.
- 16 Roy M, Waldschmidt T, Aruffo A, Ledbetter JA, Noelle RJ. The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol 1993; 151: 2497–510.
- 17 Roy M, Aruffo A, Ledbetter JA, Linsley P, Kehry M, Noelle RJ. Studies on the independence of gp39 and B7 expression and function during antigen-specific immune responses. Eur J Immunol 1995; 25: 596–603.
- 18 Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol 1985; 37: 269–390.
- 19 Mohan C, Shi Y, Laman JD, Datta SK. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 1995; 154: 1470–80.
- 20 Early GS, Zhao W, Burns CM. Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice. Response correlates with the absence of an anti-antibody response. J Immunol 1996; 157: 3159–64.
- 21 Daikh DI, Finck BK, Linsley PS, Hollenbaugh D, Wofsy D. Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 1997; 159: 3104–8.
- 22 Kalled SL, Cutler AH, Datta SK, Thomas DW. Anti-CD40 ligand antibody treatment of SNF1 mice with established nephritis: preservation of kidney function. J Immunol 1998; 160: 2158–65.
- 23 Becher B, Durell BG, Noelle RJ. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 2002; 110: 493–7.
- 24 Rudofsky UH, Evans BD, Balaban SL, Mottironi VD, Gabrielsen AE. Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization. Lab Invest 1993; 68: 419–26.
- 25 Sinha J, Wang X, Huang W, Schiffer L, Davidson A. Short term costimulatory blockade combined with cyclophosphamide does not abrogate glomerular deposition of antibodies but attenuates the kidney inflammatory response[abstract]. Arthritis Rheum 2001; 44 Suppl 9: S397.
- 26 Wang X, Huang W, Mihara M, Sinha J, Davidson A. Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus. J Immunol 2002; 168: 2046–53.
- 27 Kalled SL, Cutler AH, Burkly LC. Apoptosis and altered dendritic cell homeostasis in lupus nephritis are limited by anti-CD154 treatment. J Immunol 2001; 167: 1740–7.
- 28 Ishida H, Muchamuel T, Sakaguchi S, Andrade S, Menon S, Howard M. Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 1994; 179: 305–10.
- 29 Lin LC, Chen YC, Chou CC, Hsieh KH, Chiang BL. Dysregulation of T helper cell cytokines in autoimmune prone NZB x NZW F1 mice. Scand J Immunol 1995; 42: 466–72.
- 30 Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 1995; 181: 839–44.
- 31 Jacob CO, McDevitt HO. Tumour necrosis factor-alpha in murine autoimmune ‘lupus’ nephritis. Nature 1988; 331: 356–8.
- 32 Boswell JM, Yui MA, Burt DW, Kelley VE. Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis. J Immunol 1988; 141: 3050–4.
- 33 Brennan DC, Yui MA, Wuthrich RP, Kelley VE. Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury. J Immunol 1989; 143: 3470–5.
- 34 Takemura T, Yoshioka K, Murakami K, Akano N, Okada M, Aya N, et al. Cellular localization of inflammatory cytokines in human glomerulonephritis. Virchows Arch 1994; 424: 459–64.
- 35 Gordon C, Ranges GE, Greenspan JS, Wofsy D. Chronic therapy with recombinant tumor necrosis factor-alpha in autoimmune NZB/NZW F1 mice. Clin Immunol Immunopathol 1989; 52: 421–34.
- 36
Kontoyiannis D,
Kollias G.
Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor.
Eur J Immunol
2000;
30:
2038–47.
10.1002/1521-4141(200007)30:7<2038::AID-IMMU2038>3.0.CO;2-K CAS PubMed Web of Science® Google Scholar
- 37 Border WA, Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest 1992; 90: 1–7.
- 38 Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 1990; 346: 371–4.
- 39 Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 1992; 360: 361–4.
- 40 Moll S, Menoud PA, Fulpius T, Pastore Y, Takahashi S, Fossati L, et al. Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis. Kidney Int 1995; 48: 1459–68.
- 41 Coimbra T, Wiggins R, Noh JW, Merritt S, Phan SH. Transforming growth factor-beta production in anti-glomerular basement membrane disease in the rabbit. Am J Pathol 1991; 138: 223–34.
- 42 Okuda S, Languino LR, Ruoslahti E, Border WA. Elevated expression of transforming growth factor-beta and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial extracellular matrix. J Clin Invest 1990; 86: 453–62.
- 43 Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A 1993; 90: 1814–8.
- 44 Yamamoto K, Loskutoff DJ. Expression of transforming growth factor-beta and tumor necrosis factor-alpha in the plasma and tissues of mice with lupus nephritis. Lab Invest 2000; 80: 1561–70.
- 45 Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 1986; 83: 4167–71.
- 46 Border WA, Noble NA. Transforming growth factor-beta in glomerular injury. Exp Nephrol 1994; 2: 13–7.
- 47 Yellin MJ, D'Agati V, Parkinson G, Han AS-Y, Szema A, Baum D, et al. Immunohistologic analysis of renal CD40 and CD40L expression in lupus nephritis and other glomerulonephritides. Arthritis Rheum 1997; 40: 124–34.
- 48 Kuroiwa T, Lee EG, Danning CL, Illei GG, McInnes IB, Boumpas DT. CD40 ligand-activated human monocytes amplify glomerular inflammatory responses through soluble and cell-to-cell contact-dependent mechanisms. J Immunol 1999; 163: 2168–75.
- 49 Kuroiwa T, Schlimgen R, Illei GG, McInnes IB, Boumpas DT. Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: implications for tubulointerstitial injury in chronic glomerulonephritides. J Immunol 2000; 164: 3323–9.
- 50 Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 1999; 189: 1639–48.
- 51 Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med 1994; 180: 1295–306.
- 52
Ruger BM,
Erb KJ,
He Y,
Lane JM,
Davis PF,
Hasan Q.
Interleukin-4 transgenic mice develop glomerulosclerosis independent of immunoglobulin deposition.
Eur J Immunol
2000;
30:
2698–703.
10.1002/1521-4141(200009)30:9<2698::AID-IMMU2698>3.0.CO;2-1 CAS PubMed Web of Science® Google Scholar
- 53 Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand[letter]. Nat Med 2000; 6: 114.
- 54 Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, et al. A short course of BG9588 (anti–CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003; 48: 719–27.
- 55 Kalunian KC, Davis JC Jr, Merrill JT, Totoritis MC, Wofsy D, for the IDEC-131 Lupus Study Group. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 3251–8.
- 56 Huang W, Sinha J, Newman J, Reddy B, Budhai L, Furie R, et al. The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus. Arthritis Rheum 2002; 46: 1554–62.
