|
CD40L (CD154, gp39), a transmembrane protein and member of the tumor necrosis factor (TNF) family, is expressed on activated CD4+ T cells, mast cells, basophils, eosinophils, natural killer (NK) cells, and activated platelets. CD40L is important for T-cell–dependent B-cell responses; a prominent function of CD40L, isotype switching, is demonstrated by the hyper–immunoglobulin M (IgM) syndrome in which CD40L is congenitally deficient. The interaction of CD40L-CD40 (on antigen-presenting cells such as dendritic cells) is essential for T-cell priming and the T-cell–dependent humoral immune response.2 Therefore, interruption of the CD40-CD40L interaction with an anti-CD40L monoclonal antibody (mAb) has been considered to be a possible therapeutic strategy in human autoimmune disease, based upon the above information and on studies in animals.
In this issue, Kuwana and colleagues (page 1229) report on a phase 1 study of anti-CD40L humanized mAb (IDEC-131/E6040) in patients with refractory ITP that allows them to link pathobiology with treatment effect. The investigators explored the in vivo effects of a cohort dose escalation (1 to 10 mg/kg) single infusion study of the effects of anti-CD40L mAb on 3 types of autoreactive T- and B-cell responses to GPIIb/IIIa at 3 time points (before treatment at day 0; after treatment at days 7 and 42) and compared them with the platelet responses. A platelet response was achieved only in 3 of the 5 patients treated at the highest dose (10 mg/kg), even though all 5 patients at this dose level had decreased numbers of B cells producing anti-GPIIb/IIIa antibodies by enzyme-linked immunospot (ELISPOT), reduced GPIIb/IIIa-induced T-cell proliferation, and decreased anti-GPIIb/IIIa antibody in vitro. No platelet increases were seen at the 3 lower doses, even though patients treated at both the 5 and 10 mg/kg doses showed these autoimmune responses to be decreased. T-cell response to an irrelevant antigen (to which there was no ongoing stimulation) was not affected by anti-CD40L. The authors speculate that failure to achieve a platelet effect at 5 mg/kg, despite suppression of the autoimmune responses, may have been related to the shorter duration of the effect. It is also likely that extravascular effects (ie, in the spleen or other parts of the reticuloendothelial system) are critical and require a higher dose. In addition, there may be a heterogeneity in the pathophysiology of ITP since the responders and nonresponders at 10 mg/kg could not be distinguished on the basis of their in vitro responses.
As the authors indicate, there are 3 reports3-5 on clinical trials using another anti-CD40L mAb (hu5c8) in patients whose ITP was substantially more refractory than those included in this study (only 7 of 20 reported here had undergone splenectomy). From these reports and unpublished data (J. B. B., January 2004) for IDEC-131/E6040, it appears that 25% to 50% of patients with refractory ITP will have platelet responses to doses of 10 to 20 mg/kg of anti-CD40L administered every 2 to 4 weeks although the responses are rarely durable. These abstracts,3-5 together with the study reported here, suggest that CD40/CD40L blockade with IDEC-131/E6040 is a potentially effective therapy for refractory ITP through selective suppression of autoreactive T cells to platelet antigens.
New York Blood Center and Weill Medical College of Cornell University
References
- Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura: role in production of anti-platelet autoantibody. J Clin Invest. 1998;102: 1393-1402.
[Abstract/Free Full Text] - Van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000;67: 2-17. [Abstract]
- George J, Raskob G, Lichtin A, et al. Safety and effect on platelet count of single-dose monoclonal antibody to CD40 ligand (ANTOVATM) in patients with chronic ITP [abstract]. Blood. 1998;92: 707a.
- Bussel J, Wissert M, Oates B, et al. Humanized monoclonal anti-CD40 ligand antibody (hu5c8) rescue therapy of 15 adults with severe chronic refractory ITP [abstract]. Blood. 1999;94: 646a.
- George J, Raskob G, Bussel J, et al. Safety and effect on platelet count of repeated doses of monoclonal antibody to CD40 ligand in patients with chronic ITP [abstract]. Blood. 1999;94: 19a.
Related Articles in Blood Online :
- Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura.
Masataka Kuwana, Shosaku Nomura, Kingo Fujimura, Toshiro Nagasawa, Yoshitomo Muto, Yoshiyuki Kurata, Shigeru Tanaka, and Yasuo Ikeda Blood 2004 103: 1229-1236.[Abstract] [Full Text]
A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis
A novel SHP-1/Grb2–dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling
A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation
Allergen exposure–induced differences in CD34+ cell phenotype: relationship to eosinophilopoietic responses in different compartments
And a final message from antithrombin
Antiangiogenic antithrombin down-regulates the expression of the proangiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells
Antibody-induced intracellular signaling works in combination with radiation to eradicate lymphoma in radioimmunotherapy
BUBR1 deficiency results in abnormal megakaryopoiesis
Cell adhesion: a partner for many
Chemokine receptor–8 (CCR8) mediates human vascular smooth muscle cell chemotaxis and metalloproteinase-2 secretion