Therapeutic CD154 for lupus: promise for the future?

Garnett Kelsoe

J Clin Invest. 2003;112(10):1480-1482. https://doi.org/10.1172/JCI20371.

Commentary

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by the production of pathogenic autoantibodies. A new study demonstrates that passive antibody specific for the TNF family member, CD154, ameliorates disease by reducing levels of self-reactive antibody in the serum. This study demonstrates a substantial potential for anti-CD154 antibody in the treatment of humoral autoimmunity.

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Therapeutic CD154 antibody for lupus: phoid tissues, binding of modifies chemotaxis, resulting promise for the future? in migration toward the zone (12), where cognate T cell–B cell inter- Garnett Kelsoe action expands both lymphocyte pop- ulations. Soon afterward, activated T Department of , Duke University, Durham, North Carolina, USA and B cells emigrate from T cell areas into the reticula of follicular dendrit- Systemic lupus erythematosus (SLE) is a prototypical systemic autoim- ic cells (FDCs) that define the B cell mune disease characterized by the production of pathogenic autoanti- follicle (Figure 1). The immigrant B bodies. A new study (see the related article beginning on page 1506) lymphocytes proliferate in the FDC demonstrates that passive antibody specific for the TNF family member, reticulum to generate nascent GCs CD154, ameliorates disease by reducing levels of self-reactive antibody and, in the process, acquire distinctive in the serum. This study demonstrates a substantial potential for anti- phenotypes, including expression of CD154 antibody in the treatment of humoral autoimmunity. the CD69 activation antigen and sev- eral differentiation markers, including J. Clin. Invest. 112:1480–1482 (2003). doi:10.1172/JCI200320371. CD38 and CD27. Remarkably, human CD38+ GC B cells can also express The autoimmune disease systemic center (GC) reaction. Indeed, GCs variable levels of CD154, especially lupus erythematosus (SLE) is charac- appear spontaneously in many under conditions of chronic stimula- terized by the production of high- strains of lupus-prone mice (1), and tion (13, 14), and appear to have the affinity IgG against dou- extraordinary numbers of GC B cells capacity for continued self-activation. ble-stranded DNA (dsDNA). Typically, and their progeny are present in the GCs become polarized into histolog- these pathogenic autoantibodies are blood of SLE patients (2). ic dark and zones (DZ, LZ). The encoded by mutated Ig genes, and the GCs are organized collections of DZ is proximal to the T cell area and frequency and pattern of mutations antigen-activated T and B lympho- contains rapidly dividing B cells called strongly suggest that the source of cytes in secondary lymphoid tissues centroblasts that express little or no autoreactive antibodies is B cells that (3) or sites of chronic inflammation surface immunoglobulin. The more have participated in the germinal (4, 5). Although transient GC-like distal LZ contains the bulk of the acti- reactions can be elicited by thymus- vated FDC network, antigen-specific Address correspondence to: Garnett Kelsoe, independent pathways (6–8), most CD4 T cells, and nondividing B cells Department of Immunology, Duke University GC responses are thymus-depend- known as . Centrocytes Medical Center 3010, Duke University, ent. GC B cells require ongoing sur- express surface immunoglobulin and Durham, North Carolina 27710, USA. Phone: (919) 613-7815; Fax: (919) 613-7878; vival and proliferation signals that are thought to be the progeny of DZ E-mail: [email protected]. depend on CD154-CD40 signaling centroblasts. In turn, selected centro- Conflict of interest: The author has declared (9). CD154, a member of the TNF cytes likely reenter the DZ and regain that no conflict of interest exists. family, is inducibly expressed on the the centroblast form. Nonstandard abbreviations used: systemic surface of CD4 T lymphocytes, The enzyme AID (activation-induced lupus erythematosus (SLE); double-stranded DNA (dsDNA); (GC); whereas its ligand, CD40, is consti- cytidine deaminase) drives both follicular dendritic cell (FDC); dark zone tutively present on B lymphocytes (SHM) and (DZ); light zone (LZ); activation-induced (reviewed in ref. 10). immunoglobulin class switch recom- cytidine deaminase (AID); somatic T cell–dependent GCs begin with bination (CSR) in GC B cells (15). hypermutation (SHM); class switch recombination (CSR); SLE disease activity the separate activation of T and B cells SHM introduces point mutations and index (SLEDAI). by antigen (11). In secondary lym- occasional small deletions into the

1480 The Journal of Clinical Investigation | November 2003 | Volume 112 | Number 10 Figure 1 Potential cellular targets for passive CD154 antibody to interrupt thymus-dependent GC and antibody responses. Antigen-specific T and B lymphocytes meet at the interface of T and B cell zones (follicles) in secondary lymphoid tissues (I). CD40-CD154 interaction results in the local proliferation of both lymphocyte types. Following clonal expansion, a fraction of activated T and B cells, prompted by CD40- CD154 signaling, migrate into the follicle to initiate the GC reaction (II). In GCs, B cells proliferate and activate AID-dependent SHM and CSR. Other clonally related B lymphocytes are retained in extra-follicular sites and differentiate into antibody-forming cells (AFCs), or plasmacytes (III). These transient AFCs do not express AID and do not support CSR and SHM. In GCs, centroblasts proliferate in the DZ, migrate to the LZ as centrocytes, present antigen to LZ T cells, and receive signals that direct either their exit from the GC or return to the DZ (IV). Centrocytes that do not receive survival signals die by apoptosis. Active GCs require continuous CD40-CD154 signaling; these signals may represent homotypic interaction between CD40+CD154+ centroblasts or heterotypic signals between CD40+ centro- cytes and CD154+CD4 T cells. Selected B cells exit the GC (V) to enter the memory or long-lived plasmacyte compartments. Grammer et al. (17) observe that passive anti-CD154 reduces the numbers of IgD+CD38+ GC precursors (I and II) and CD38bright plasmacytes (III and V) but has little effect on circulating GC (IgD–CD38+) cells (IV). The primary effect(s) of CD154 antibody in SLE patients may be to inter- rupt the early initiation (I) and/or migrations steps (II) of the GC reaction.

V(D)J regions of transcriptionally antibody and are capable of main- and scores on a standardized index of active immunoglobulin genes. Muta- taining significant levels of serum SLE activity (SLEDAI) remained sig- tions are probably introduced in cen- antibody for years, if not decades. nificantly suppressed over a 20-month troblasts and accumulate during Characteristically, fully differentiated post-treatment period. These promis- repeated rounds of centroblast/cen- human plasmacytes express high lev- ing results are tempered by the fact trocyte migration between the DZs els of CD38. that this clinical study was premature- and LZs (Figure 1). Intense selection ly ended due to adverse side effects for higher-affinity mutants establish- Passive CD154 antibody (16). Nonetheless, the substantial clin- es GCs as foci of rapid somatic evolu- therapy for lupus ical improvements observed by Gram- tion and antibody affinity maturation. In this issue of the JCI, Amrie Gram- mer et al. suggest a therapeutic strate- CSR ensures that mutated, high-affin- mer and colleagues demonstrate that gy of considerable potential. But how, ity antibodies acquire various effec- administration of a humanized mon- and where, does anti-CD154 antibody tor activities and can be delivered oclonal antibody specific for CD154 ameliorate SLE? throughout the body. (16) produced significant clinical ben- With time, centrocytes leave GCs efit in a small group of active SLE Potential cell targets and enter into at least two phenotyp- patients (17). Anti-CD154 promptly for anti-CD154 ically distinct compartments of mem- decreased levels of dsDNA serum auto- There are at least three stages of ory cells (Figure 1). One compart- antibody and also diminished the humoral immune responses in which ment, comprising antigen-specific, numbers of GC B cells and plasma- interruption of CD154-CD40 signals small, resting B lymphocytes, defines cytes circulating in the blood. While can abrogate the GC reaction and the classical memory B lymphocyte. dsDNA antibody levels rebounded antibody responses (Figure 1). Anti- The other contains long-lived plas- after treatment, other objective meas- CD154 can (i) interrupt the initial, macytes that secrete high-affinity ures of disease including proteinuria cognate interaction between antigen-

The Journal of Clinical Investigation | November 2003 | Volume 112 | Number 10 1481 specific T and B lymphocytes within development are deleted by apoptosis 6. de Vinuesa, C.G., et al. 2000. Germinal centers without T cells. J. Exp. Med. 191:485–494. and/or adjacent to the T cell areas of (18), enfeebled (19), or given a new 7. Toellner, K.M., et al. 2002. Low-level hypermuta- lymph nodes or spleen. Blockade of reactivity by receptor editing (20). tion in T cell-independent germinal centers com- this interaction prevents both the for- SHM in GC B cells must occasionally pared with high mutation rates associated with T cell-dependent germinal centers. J. Exp. Med. mation of GCs and the initial produc- produce autoreactive antigen-recep- 195:383–389. tion of plasmacytes. Later in the tors absent from the tolerizing envi- 8. Lentz, V.M., and Manser, T. 2001. Cutting edge: germinal centers can be induced in the absence of response, anti-CD154 disrupts GCs ronment of the bone marrow. 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Science. 281:96–99. – + change in the numbers of IgD CD38 their affinity maturation into patho- 12. Reif, K., et al. 2002. Balanced responsiveness to blood cells in SLE patients but rather genic forms. chemoattractants from adjacent zones deter- mines B-cell position. Nature. 416:94–99. causes substantial reductions in the Regardless of where, or even how, 13. Grammer, A.C., McFarland, R.D., Heaney, J., Dar- numbers of IgD+CD38+ cells and passive antibody to CD154 acts to nell, B.F., and Lipsky, P.E. 1999. Expression, reg- CD38high plasmacytes. Reductions in reduce SLE disease, Grammer and col- ulation, and function of B cell-expressed CD154 in germinal centers. J. Immunol. 163:4150–4159. these pre-switch GC cells and plasma- leagues have taken an important step 14. Desai-Mehta, A., Lu, L., Ramsey-Goldman, R., cytes correlate with reductions in toward defining the promise of and Datta, S.K. 1996. Hyperexpression of CD40 ligand by B and T cells in human lupus and its autoantibody titers and DNA-specific CD154-CD40 interaction as a target role in pathogenic autoantibody production. blood plasmacytes (16). The biased of therapy (17). The future is not clear J. Clin. Invest. 97:2063–2073. effects on pre-switch cells and plas- — the antibody used in these studies 15. Muramatsu, M., et al. 2000. Class switch recom- bination and hypermutation require activation- macytes suggests that the primary elicited unacceptable side effects — induced cytidine deaminase (AID), a potential benefit of anti-CD154 treatment in but the direction of study has been RNA editing enzyme. Cell. 102:553–563. SLE may be the disruption of plasma- clearly defined. If different autoim- 16. Boumpas, D.T., et al. 2003. 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