drug is concentrated in the central nervous system at theoretically
`efficacious levels, and the intranasal route holds promise for
`outpatient studies. These data argue for expanded testing of peptide
`T in AIDS and other HIV infected, less immunologically
`suppressed, neuropsychiatrically impaired persons, which is now
`underway.
`
`Intramural Research Program,
`National Institute of Mental Health,
`Bethesda, Maryland 20892, USA;
`University of Southern California,
`Los Angeles County Medical Center,
`Los Angeles, California,
`and Integra Institute,
`Germantown, Maryland
`
`T. PETER BRIDGE
`PETER N. R. HESELTINE
`ELIZABETH S. PARKER
`ELAINE EATON
`LORING J. INGRAHAM
`MARK GILL
`MICHAEL RUFF
`CANDACE B. PERT
`FREDERICK K. GOODWIN
`
`1. Pert C, Hill J, Ruff M, et al. Octopeptides deduced from the neuropeptide
`receptor-like pattern of antigen T4 in brain potently inhibit human
`immunodeficiency virus receptor binding and T-cell infectivity. Proc Natl Acad
`Sci (USA) 1986; 83: 9254-58.
`2 Ruff M, Martin B, Ginns E, et al. CD4 receptor binding peptides that block HIV
`infectivity cause monocyte chemotaxis. FEBS Lett 1987; 211: 17-22.
`3 Ruff M, Hallberg P, Hill J, et al. Peptide T is core HIV envelope required for CD4
`receptor attachment. Lancet 1987; ii: 751.
`4. Brenneman D, Westerbrook G, Fitzgerald S, et al. Neuronal killing by the enveloped
`protein of HIV and its prevention by vasoactive intestinal peptide. Nature 1988;
`335: 639-42.
`5. Brenneman D, Buzy J, Ruff M, et al. Peptide T sequences prevent neuronal cell death
`produced by the protein (gp 120) of the Human Immunodeficiency Virus. Drug
`Dev Res 1988; 15: 361-69.
`
`RAPAMYCIN FOR IMMUNOSUPPRESSION IN
`ORGAN ALLOGRAFTING
`SIR,-Rejection
`of
`complications
`infective
`and
`immunosuppressive treatment are the main causes of failure in
`organ allografting in man. To minimise the individual side-effects,
`azathioprine, corticosteroids, and cyclosporin are combined in small
`doses. Cyclosporin is the most powerful agent of the three, but can
`be nephrotoxic. No other immunosuppressants are useful clinically
`because of toxicity and/or lack of efficacy.
`The fungal product, FK506, is immunosuppressive in animals
`with organ grafts.’ We confirmed the immunosuppressive effect but
`animal toxicity was too severe to proceed to clinical trial,z although
`such a study is now underway in the USA. A compound with
`structural similarities to FK506, rapamycin, was investigated on the
`basis of a report that it inhibited experimental allergic encephalitis,
`adjuvant arthritis, and the formation of humoral antibody in rats.3
`Rapamycin is a lipophilic macrolide produced by Streptomyces
`hygroscopicus with both antifungal and antitumour properties.4
`rapamycin
`administration,
`intramuscular
`After
`was
`immunosuppressive in rats given heterotopic heart allografts
`(table). Graft survival, assessed by palpation of the beating heart,
`was prolonged in all animals given rapamycin beyond the control
`period of 7-4 days. Toxicity in the rat was mild: weight loss of less
`than 10% was observed in the group treated with the highest dose.
`Non-immunosuppressed nephrectomised pigs with major
`histocompatibility complex incompatibles renal allografts die from
`uraemia due to rejection within a mean survival time of 15’ 1 days.b
`Survival times of treated pigs (mean 76 days, median 55) and causes
`of death are shown in the table, with current creatinine values of
`surviving animals. Three animals survived with normal serum
`creatinine levels, after not receiving any drug for 6 months. One
`kidney was rejected early, on day 4. The interstitial pneumonitis in
`five pigs was probably due to over-immunosuppression. There was
`no histological or biochemical evidence of rejection in four of these
`animals and a mild degree of cellular reaction in the fifth, which had
`had its immunosuppression stopped. Dogs had vomiting and
`diarrhoea associated with ulceration of the mouth and
`thrombocytopenia after daily oral doses of 0-25-5 mg/kg. At
`necropsy all the dogs had gastrointestinal ulcers from the mouth to
`the colon, secondary to acute necrotising fibrinoid vasculitis of
`arterioles and small arteries. The lesions were present even in dogs
`treated with an apparently non-immunosuppressive regimen of
`2 mg;kg on days 3-5 (table).
`
`SURVIVAL OF ALLOGRAFTS
`
`227
`
`Major pathological findings: * = rejection; t = interstitial pneumonitis but no vasculitis;
`and = toxicity. Latest creatinine (pool/1): 141O, 161, 235, 176, 239, 283, 220, 137, and
`148; ¶294, 503, 1758, 1708, 1388, 871, and 541.
`
`Like FK506, rapamycin is a powerful immunosuppressant that is
`especially toxic in dogs. The vasculitic lesions, however, were
`largely confmed to the gastrointestinal tract with rapamycin,
`whereas with FK506 vasculitis was widespread, including in the
`heart.2 If rapamycin, which appears to have little toxicity in
`primates (Dr J. Chang, Wyeth-Ayerst), is found to have a
`satisfactory
`therapeutic index and is
`effective
`as an
`immunosuppressant in primates with organ allografts, then the
`compound has potential clinical use. Vasculitis in the dog remains a
`worry and raises the question of a species idiosyncratic reaction.
`We thank Dr Joseph Chang and Dr Surendra N. Seghal of Wyeth-Ayerst
`Research, Pnnceton, New Jersey, for helpful discussion and supply of drugs.
`D. ST. J. COLLIER
`R. Y. CALNE
`SUSAN LIM
`S. G. POLLARD
`D. J. G. WHITE
`A. SAMAAN
`SATHIA THIRU
`
`Department of Surgery,
`Addenbrooke’s Hospital,
`Cambridge CB2 2QQ
`
`1. Ochiai T, Sakamoto K, Nagata M, et al. Studies on FK506 in experimental organ
`transplantation. Transplant Proc 1988; 20: 209-14.
`2. Collier DStJ, Calne RY, Thiru Sathia, et al. FK506 in experimental renal allografts in
`dogs and primates. Transplant Proc 1988; 20: 226-28.
`3. Martel RR, Klicius J, Galet S. Inhibition of the immune response by rapamycin, a new
`antifungal antibiotic. Can J Physiol Pharmacol 1977; 55: 48-51.
`4. Eng CP, Sehgal SN, Vézna C. Activity of rapamycin (AY-22,989) against transplanted
`tumors. J Antibiol 1984; 37: 1231-37
`5. Bradley BA, White DJG, Edwards JM. Restriction of polymorphism defined by
`mixed lymphocyte reactions in the pig. Tissue Antigens 1974; 4: 283-90.
`6. White DJG, Bradley BA, Calne RY, et al. The relationship of the histocompatibility
`locus in the pig to allograft survival. Transplant Proc 1973; 5: 317-20.
`7. Heron I. Acta Pathol Microbiol Scand 1971; 79: 366.
`8. Calne RY, Sells RA, Marshall VC, et al. Multiple organ grafts in the pig. Br J Surg
`1972; 59: 969-77.
`9. Calne RY, Alexandre GPJ, Murray JE. A study of the effects of drugs in prolonging
`survival of homologous renal transplants in dogs. Ann NY Acad Sci 1962; 99:
`743-61.
`
`LEWIS NEGATIVE GENOTYPE AND BREAST
`CANCER RISK
`SIR,-Mr Phipps and Mr Perry’s data (May 27, p 1198) support
`an association between the Lewis negative genotype and breast
`cancer, but their findings have been challenged by Prof Petrakis et al
`(July 1, p 41). There are difficulties in the genetic interpretation of
`Lewis phenotypes, and they preclude the use of this system in
`paternity and forensic studies. Lewis antigens are adsorbed onto the
`red cell surface from the plasma and the Le(a - b + ) phenotype can
`only arise by interaction between the products of Le, Se, and H
`genes. Since only one Le gene exists Phipps and Perry’s hypothesis
`is that the Lewis negative genotype is due to a chromosomal deletion
`should mean that the observed increase in the Le(a-b-)
`phenotype would be equally shared from the Le(a+b-) and
`Le(a - b +) pool of patients. Saliva studies, which are the most
`reliable way to Lewis type patients as long as one is aware that
`Le(a - b +) people will secrete Lea as well as Leb substance, show
`the increase in the Le(a - b - ) phenotype to be solely at the expense
`
`West-Ward Exhibit 1053
`Calne 1989
`Page 001
`
`