Effects on T-cell maturation and proliferation induced by lactational transfer of cyclosporine to nursing pups.
BACKGROUND
Pregnancy after allotransplantations is becoming a more common occurrence, and the immunosuppressant of choice is cyclosporine (CsA) for these patients. Consequently, the effect of CsA on prenatal and postnatal immune development and function in the infant is an increasingly important clinical issue. The purpose of this study was to evaluate the potential problems of maternal CsA exposure on neonatal T-cell maturation and proliferation after lactational transfer of CsA in an animal model.


METHODS
CsA was administered daily (subcutaneous) for 20 days during lactation, beginning the day of parturition using two dose levels (15 and 25 mg/kg body weight/day) in conjunction with saline controls.


RESULTS
Considerable amounts of CsA were passed to the newborn rats with neonatal blood levels equal to that of the mothers for the 25-mg/kg/day dose and 55% for the 15 mg/kg dose. There was a significant reduction in thymus/body-weight ratio and thymus cellularity for the pups born to mothers dosed at 15 or 25 mg/kg/day of CsA. The thymus from the CsA-exposed pups showed an almost complete loss of the medullary region with no apparent change in the thymic cortex. The CsA-treated mothers and their pups (15 and 25 mg/kg/day dose) had a significant increase in the percentage of CD4+CD8+ thymocytes and a significant decrease in the percentages of CD4+, CD3hi, and T-cell receptor (TCR)hi thymocyte phenotype subsets and CD4/CD8 ratios. Thymocyte proliferative responses to concanavalin A + interleukin-2 were also significantly decreased in the mother and pup after both doses of CsA. In contrast to the mothers that showed no change in splenocyte proliferative responses, their pups showed decreased responses at both the 15- and 25-mg/kg doses. All immune alterations due to CsA lactational exposure in the pups were back to control levels after 30 days of postweaning CsA cessation.


CONCLUSIONS
This study clearly demonstrates that neonatal exposure to CsA via lactational transfer can cause significant alterations in T-cell maturation and inhibition of lymphoproliferative responsiveness to mitogen activation. Although the CsA blood level in human transplant patients is normally much lower, this data indicate a potential for increased risk to opportunistic infections due to altered immune components in babies exposed to long-term CsA.
Padgett
Eric L
EL
Wil Research Laboratories, Inc., Ashland, OH 44805-9281, USA.
Seelig
Leonard L
LL
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016130:Immunophenotyping; D007774:Lactation / Q000276:immunology*; D008098:Litter Size; D008213:Lymphocyte Activation / Q000187:drug effects; D023421:Models, Animal; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects / Q000276:immunology*
D016572:Cyclosporine