Correspondence

More on Anti–Glomerular Basement Membrane Disease after Alemtuzumab

N Engl J Med 2008; 359:2501-2502December 4, 2008

Article

To the Editor:

Clatworthy et al. (Aug. 14 issue)1 report on two patients (one with multiple sclerosis and the other with antineutrophil cytoplasmic antibody–associated vasculitis) in whom anti–glomerular basement membrane nephritis developed after treatment with alemtuzumab. The authors speculate that the emergence of autoreactive B cells rather than persistently suppressed T cells after alemtuzumab therapy might have caused autoimmunity in their patients. However, the production of anti–glomerular basement membrane autoantibodies has been associated with a deficiency of suppressor T cells.2 Ligler et al. found that the production of anti–glomerular basement membrane autoantibodies decreased and then stopped as the percentage of OKT8+ cells (suppressor and cytotoxic T cells) returned to normal levels.2 In the two patients described by Clatworthy et al., the number of CD8+ T lymphocytes was low (190 and 80 cells per cubic millimeter; normal range, 200 to 900), but the number of CD19+ cells was within the normal range. Since alemtuzumab could eliminate about 77% of CD8+ T lymphocytes by means of non–complement-mediated mechanisms,3 persistently suppressed CD8+ T cells could have influenced the development of anti–glomerular basement membrane antibodies in their patients.

Jae Il Shin, M.D.
Jae Seung Lee, M.D.
Yonsei University College of Medicine, Seoul 120-752, Korea
pedshin2000@yahoo.co.kr

3 References

1
Clatworthy MR, Wallin EF, Jayne DR. Anti-glomerular basement membrane disease after alemtuzumab. N Engl J Med 2008;359:768-769
Full Text | Web of Science | Medline

2
Ligler FS, Westby GR, Hertz BC, Durning CM, Cohen R, Bonner H. Immunoregulatory cell subsets in Goodpasture's syndrome: evidence for selective T suppressor-cell depletion during active autoimmune disease. J Clin Immunol 1983;3:368-374
CrossRef | Web of Science | Medline

3
Lowenstein H, Shah A, Chant A, Khan A. Different mechanisms of Campath-1H-mediated depletion for CD4 and CD8 T cells in peripheral blood. Transpl Int 2006;19:927-936
CrossRef | Web of Science | Medline

Author/Editor Response

Shin and Lee suggest that the development of anti–glomerular basement membrane disease in two patients treated with alemtuzumab was due to a deficiency of CD8 suppressor T cells. The speculation is based on a description of a patient with atypical, spontaneously resolving, anti–glomerular basement membrane disease in which low levels of so-called CD8 suppressor T cells were observed.1 The OKT8 antibody that was used to define suppressors in this article merely identifies CD8 T cells, with no demonstration of a deficiency of suppressor function within this subgroup. Aside from the limitations of this article, CD8 T-cell depletion actually prevents or ameliorates disease in animal models of anti–glomerular basement membrane disease.2 In addition, data suggest that CD8 regulatory T cells in humans reside in the CD8+CD28− T-cell compartment.3 After treatment with alemtuzumab, this regulator-containing CD8+CD28− subgroup is enriched within the reconstituted CD8 T-cell compartment.4

Since acceptance of our letter, we have become aware that one of our two patients was previously mentioned in the adverse-effects section of an article on alemtuzumab in multiple sclerosis.5

Menna R. Clatworthy, M.B., Ch.B., Ph.D.
University of Cambridge, Cambridge CB2 2XY, United Kingdom
mrc38@cam.ac.uk

Elizabeth F. Wallin, M.B., B.Chir.
David R. Jayne, M.D.
Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom

5 References

1
Ligler FS, Westby GR, Hertz BC, Durning CM, Cohen R, Bonner H. Immunoregulatory cell subsets in Goodpasture's syndrome: evidence for selective T suppressor-cell depletion during active autoimmune disease. J Clin Immunol 1983;3:368-374
CrossRef | Web of Science | Medline

2
Reynolds J, Norgan VA, Bhambra U, Smith J, Cook HT, Pusey CD. Anti-CD8 monoclonal antibody is effective in the prevention and treatment of experimental autoimmune glomerulonephritis. J Am Soc Nephrol 2002;13:359-369
Web of Science | Medline

3
Chang CC, Ciubotariu R, Manavalan JS, et al. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 2002;3:237-243
CrossRef | Web of Science | Medline

4
Trzonkowski P, Zilvetti M, Chapman S, et al. Homeostatic repopulation by CD28-CD8+ T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression. Am J Transplant 2008;8:338-347
CrossRef | Web of Science | Medline

5
Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006;253:98-108
CrossRef | Web of Science | Medline

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