90 80 70 Mt5178A 60 Mt5178C 50 40 30 20 10 0 0 50 100 150 200 Cumulative number )sraey( egA

preparations administered to individual patients by the amount of IVIG each patient received during the 5 days resulted in a mean of 15·71 mg total (active and latent) TGF(cid:2) (52% TGF(cid:2)1, 48% TGF(cid:2)2) received by the patients during the course of therapy.

We can now report that the powerful immunosuppressive cytokine TGF(cid:2) is present in substantial amounts in commercially available IVIG preparations. Since immunoglobulin has been described as a carrier of TGF(cid:2),4 the high concentrations of TGF(cid:2) in IVIG may initially be delivered by IVIG, namely by the immunoglobulin-bound cytokine. Because our experiments disclosed no adherence of TGF(cid:2) to IgG, the methods for the manufacture and long- term storage of IVIG may facilitate the dissociation of TGF(cid:2) non-specifically bound to IgG. The inference that TGF(cid:2) contributes to the therapeutic effects of IVIG therapy is supported by the results of various animal studies on autoimmune diseases,5 in which the administration of TGF(cid:2) led to increased immunosuppression similar to that seen under IVIG therapy. Although TGF(cid:2)-containing IVIG preparations may be useful in the treatment of autoimmune diseases, their value in the treatment of other disorders is unknown. It remains for future clinical trials to compare the effects of IVIG preparations with and without TGF(cid:2) or to apply TGF(cid:2) alone in the treatment of human autoimmune diseases.

diseases—and thereby life span of the individual. examine this hypothesis, we analysed mtDNA from Japanese centenarians.

The entire coding regions of mtDNA, including two rRNA genes, 22 tRNA genes, and 13 protein-coding genes, from 11 centenarians were sequenced by fluorescence- based automated direct sequencing.3 Although there were a variety of nucleotide substitutions, we identified several that were more frequent among these centenarians than among the 43 controls whose mtDNA sequences had been analysed.4 Two nucleotide substitutions causing aminoacid replacements (a C-to-A transversion at nucleotide position [np] 5178 within the NADH dehydrogenase subunit 2 gene [ND2], causing Leu-to-Met replacement; and a C-to-T transition at np 8414 within the ATP synthase subunit 8 gene [ATP8], causing Leu-to-Phe replacement) as well as a G-to-A transition at np 3010 within the 16S rRNA gene, were more frequently observed in the centenarians than in the controls (Mt5178A in 9/11 centenarians vs 12/43 controls, p<0·01; Mt8414T in 7/11 centenarians vs 11/43 controls, p<0·05; and Mt3010A in 7/11 centenarians vs 11/42 controls, p<0·05). Most of these variations were linked; all of the seven centenarians with both Mt8414T and Mt3010A carried Mt5178A.

This work was supported by a grant from the Bundesministerium für Forschung und Technologie, Bonn, Germany (01 kd 89030). We thank Thilo Kähne and Kathleen Bartels for their technical help.

Mouthon L, Kaveri SV, Spalter SH, et al. Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clin Exp Immunol

;

:

–

Szymkowiak C, Mons I, Gross WL, Kekow J. Determination of transforming growth factor (cid:

)

determination in human blood samples by ELISA. J Immunol Methods

;

:

–

Pap T, Zimmerman E, Spieler W, Keitel W, Kekow J. Short-term efficacy of intravenous immunoglobulin therapy in patients with rheumatoid arthritis. In: Machtey I, ed. Progress in rheumatology. Petah Tiqva, Israel: Rheumatology Service, Golga Campus,

:

–

Stach RM, Rowley DA. A first or dominant immunization. II. Induced immunoglobulin carries transforming growth factor beta and suppresses cytolytic T cell responses to unrelated alloantigens. J Exp Med

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:

–

Kekow J, Wiedemann GJ. Transforming growth factor (cid:

): a cytokine with multiple actions in oncology and potential clinical applications. Int J Oncol

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Among these variations, we focused on Mt5178A and screened 37 centenarians and 252 healthy blood donors in Aichi Prefecture for the presence of Mt5178A by PCR- restriction fragment length polymorphism (PCR-RFLP) with AluI. The frequency of Mt5178A was significantly higher in centenarians (23/37, 62%) than in blood donors (114/252, 45% p=0·04, odds ratio 1·99). This finding suggests that Mt5178A is related to longevity.

Clinic of Rheumatology (J Kekow) and Institute of Experimental Medicine, University of Magdeburg, 39245 Vogelsang/Magdeburg, Germany

Mitochondrial genotype associated with longevity

To evaluate the effect of mtDNA variations on the occurrence of diseases, we analysed the frequencies of Mt5178A and Mt5178C in 338 randomly selected inpatients and outpatients at Nagoya University Hospital. The age distribution of the patients with Mt5178A or Mt5178C (figure) indicated that the frequency of Mt5178C was almost the same as that of Mt5178A among the young patients (Mt5178 A:C ratio 46:40 for patients aged <46), whereas the frequency of Mt5178C increased more markedly than that of Mt5178A among old patients (Mt5178 A:C ratio 86:166 for patients aged (cid:5)46) with a clear reflection point at age 45. The ratio of Mt5178 A/C was significantly lower in the old patients (Mt5178 ratio 86:166) than in both the centenarians (23:14, p=0·001) and the healthy controls (114:138, p=0·01). This result suggests that the individuals with Mt5178C are more susceptible to adult-onset diseases than those with Mt5178A.

Masashi Tanaka, Jian-Sheng Gong, Jin Zhang, Makoto Kunio Yagi