Yuh D D, Gandy K L, Reitz B A, Hoyt G, Robbins R C
Department of Cardiothoracic Surgery, Stanford University Medical Center, Calif 94305, USA.
J Thorac Cardiovasc Surg. 1997 Jul;114(1):64-75. doi: 10.1016/S0022-5223(97)70118-1.
Tolerance appears to be more easily induced in the fetus before full immunocompetence is established, but elucidation of this process is needed. A model of perinatal tolerance induction to neonatal skin allografts followed by cardiac and pulmonary allografts is described.
Sixty Lewis (RT11) rat fetuses were inoculated intraperitoneally at 18 days gestation with 1 x 10(7) ACI (RT1a) rat fetal liver cells (group I); 20 Lewis fetuses were inoculated with 2 x 10(7) ACI fetal liver cells (Group II). control groups consisted of Lewis fetuses inoculated with saline solution (n = 25, group III) and fetuses that were not inoculated (n = 25, group IV). Twenty-five of the 50 surviving group I rats received ACI skin (< 24 hours old) and heart (8 to 10 weeks old) allografts (group IA); the remaining 25 rats received only ACI heart grafts (group IB). Groups II, III, and IV received ACI skin and cardiac allografts. Recipients tolerant to both skin and cardiac grafts received orthotopic ACI lung grafts and third-party skin grafts. Tolerance was indicated by graft survival for more than 100 days. Limiting dilution and flow cytometric analyses were performed.
Abortion rates in groups I, II, III, and IV were 17% (10/60), 65% (13/20), 8% (2/25), and 4% (1/25), respectively. Specific tolerance to skin, cardiac, and lung allografts was observed in seven of 25 group IA recipients (28%) and seven of seven group II recipients (100%) compared with no tolerance in any group IB, III, or IV recipients (p = 0.03, chi 2 test). A 100-fold reduction of precursor cytotoxic T lymphocytes and significant splenocyte and bone marrow chimerism in tolerant versus nontolerant rats were noted (p = 0.0001, Student's t test).
Using donor-strain fetal liver cells and neonatal skin grafts, we achieved higher frequencies of tolerance to solid organ grafts in adulthood with lower cell inocula and abortion rates than previously described. Chimerism and depressed precursor cytotoxic T lymphocyte frequencies in tolerant recipients suggest that hematopoietic stem cell engraftment and clonal deletion/anergy are involved in induction of perinatal tolerance.
在完全免疫能力建立之前，胎儿似乎更容易诱导产生耐受性，但这一过程仍需阐明。本文描述了一种围产期诱导对新生儿皮肤同种异体移植物耐受性，随后对心脏和肺同种异体移植物产生耐受性的模型。
60只妊娠18天的Lewis（RT11）大鼠胎儿经腹腔接种1×10⁷个ACI（RT1a）大鼠胎儿肝细胞（I组）；20只Lewis胎儿接种2×10⁷个ACI胎儿肝细胞（II组）。对照组包括接种盐溶液的Lewis胎儿（n = 25，III组）和未接种的胎儿（n = 25，IV组）。I组50只存活大鼠中的25只接受ACI皮肤（<24小时龄）和心脏（8至10周龄）同种异体移植物（IA组）；其余25只大鼠仅接受ACI心脏移植物（IB组）。II组、III组和IV组接受ACI皮肤和心脏同种异体移植物。对皮肤和心脏移植物均耐受的受体接受原位ACI肺移植物和第三方皮肤移植物。移植物存活超过100天表明产生了耐受性。进行了极限稀释和流式细胞术分析。
I组、II组、III组和IV组的流产率分别为17%（10/60）、65%（13/20）、8%（2/25）和4%（1/25）。与IB组、III组或IV组受体均无耐受性相比，25只IA组受体中有7只（28%）以及7只II组受体中有7只（100%）观察到对皮肤、心脏和肺同种异体移植物的特异性耐受性（p = 0.03，卡方检验）。与未耐受大鼠相比，耐受大鼠的前体细胞毒性T淋巴细胞减少了100倍，脾细胞和骨髓嵌合体显著（p = 0.0001，学生t检验）。
使用供体品系胎儿肝细胞和新生儿皮肤移植物，我们在成年期实现了对实体器官移植物更高频率的耐受性，且细胞接种量和流产率均低于先前报道。耐受受体中的嵌合体和前体细胞毒性T淋巴细胞频率降低表明，造血干细胞植入以及克隆缺失/失能参与了围产期耐受性的诱导。
