Hewitt C W, Llull R, Patel M P, Beko K R, Black K S, Martin D C
Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, Cooper Hospital, Camden, NJ 08103, USA.
Transpl Int. 1994;7 Suppl 1:S559-62. doi: 10.1111/j.1432-2277.1994.tb01443.x.
Multiple pretransplant blood transfusions while under limited daily cyclosporine cover (PTBT-CsA) induce extensive rat renal allograft survival and antigen-specific non-responsiveness. The underlying mechanisms of this extensive allograft survival are not yet fully understood. We hypothesized that one of the potential contributing mechanisms to tolerance induction in PTBT-CsA-treated kidney recipients is the development of stable mixed chimerism, putatively due to the proliferation of stem cells capable of haematopoiesis in the transfused blood. BN rats served as whole blood and kidney donors. LEW rats served as recipients of the PTBT-CsA protocol and BN kidney transplants. Three weekly transfusions were given under concomitant limited CsA cover. Following these multiple primary sensitizations, antigen-specific splenic cellular responsiveness in vivo was normal in comparison with naive animals. However, these experimental splenocytes were non-specifically suppressed against third-party allodeterminants. At 100 days post-transplantation (T100) following tolerance induction to kidney allografts (secondary challenge), in vivo adoptive transfer experiments demonstrated the existence of potent splenic suppressor cells. In vitro suppressor cell assays confirmed that these cells were non-specific suppressor cells. However, following chimerism stabilization at T130, splenic antigen-specific suppressor cells became exclusively expressed in the tolerant animals, replacing the non-specific suppressor cells. At this time, splenic microchimerism was at peak levels and remained stable from T100 to T130. In conclusion, these findings demonstrate that sequential mechanisms of suppressor cell network expression are induced within a chimeric environment by blood-CsA immune modulation. Stable mixed lymphocyte chimerism and related immunomodulatory mechanisms may, therefore, play an important tolerogenic role in blood-CsA-induced non-responsiveness and in the beneficial effect of blood transfusion.
在每日有限剂量环孢素覆盖下进行多次移植前输血（PTBT-CsA）可诱导大鼠肾移植长期存活以及抗原特异性无反应性。这种移植长期存活的潜在机制尚未完全明确。我们推测，PTBT-CsA处理的肾移植受者诱导耐受的潜在机制之一是稳定混合嵌合体的形成，推测这是由于输入血液中能够造血的干细胞增殖所致。BN大鼠作为全血和肾脏供体。LEW大鼠作为PTBT-CsA方案及BN肾移植的受者。在同时给予有限剂量环孢素的情况下每周输血3次。经过这些多次初次致敏后，与未致敏动物相比，体内抗原特异性脾细胞反应性正常。然而，这些实验性脾细胞对第三方同种异体抗原决定簇被非特异性抑制。在对肾移植诱导耐受（二次攻击）后的移植后100天（T100），体内过继转移实验证明存在强效脾抑制细胞。体外抑制细胞试验证实这些细胞是非特异性抑制细胞。然而，在T130嵌合体稳定后，脾抗原特异性抑制细胞仅在耐受动物中表达，取代了非特异性抑制细胞。此时，脾微嵌合体处于峰值水平，并从T100到T130保持稳定。总之，这些发现表明，血液-环孢素免疫调节在嵌合环境中诱导了抑制细胞网络表达的相继机制。因此，稳定的混合淋巴细胞嵌合体及相关免疫调节机制可能在血液-环孢素诱导的无反应性以及输血的有益作用中发挥重要的致耐受作用。
