Prigozhina Tatyana B, Elkin Gregory, Khitrin Sofia, Slavin Shimon
Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Hospital, Jerusalem, Israel.
Exp Hematol. 2004 Nov;32(11):1110-7. doi: 10.1016/j.exphem.2004.07.017.
New nonmyeloablative strategies to improve acceptance of mismatched bone marrow (BM) may compensate for the inadequate supply of compatible grafts. Recently we proposed to facilitate engraftment of mismatched BM by selective depletion of activated donor-reactive host cells with cyclophosphamide (CY). Here we have compared engraftment of allogeneic BM after depletion of antigen-activated host lymphocytes by CY, with BM engraftment following general immunosuppression by the same CY dose.
Naive or mildly irradiated BALB/c mice were primed with C57BL/6 BM cells (day 0), treated with CY in order to deplete activated T cells (day 1), and transplanted with a second C57BL/6 BM inoculum (day 2) in order to achieve BM engraftment. Alternatively, mice received an equal dose of donor BM cells in a single injection one day after the same CY dose. Treated animals were repeatedly tested for persistence of donor cells in the blood.
Depletion of alloantigen-primed lymphocytes by 200 mg/kg CY provided stable GVHD-free engraftment of allogeneic BM in nonirradiated mice, while immunosuppressive treatment with the same CY dose alone resulted in BM rejection. Low-dose irradiation before priming with donor BM allowed the tolerance-inducing CY dose to be reduced to 100 mg/kg. Alloantigen-primed lymphocyte depletion (APLD) by a reduced CY dose resulted in engraftment of donor BM after a significantly lower irradiation dose than treatment with irradiation and CY alone.
Our results demonstrate that conditioning that focuses on APLD has a definite advantage over general immunosuppression with CY and radiation therapy.
新的非清髓性策略可提高对不匹配骨髓（BM）的接受度，这可能弥补相匹配移植物供应不足的问题。最近我们提出，通过用环磷酰胺（CY）选择性清除活化的供体反应性宿主细胞，来促进不匹配BM的植入。在此，我们比较了用CY清除抗原活化的宿主淋巴细胞后同种异体BM的植入情况，与用相同剂量CY进行全身免疫抑制后BM的植入情况。
将未致敏或轻度照射的BALB/c小鼠用C57BL/6 BM细胞进行预处理（第0天），用CY处理以清除活化的T细胞（第1天），并移植第二次C57BL/6 BM接种物（第2天）以实现BM植入。或者，小鼠在相同CY剂量后一天单次注射等量的供体BM细胞。对处理过的动物反复检测血液中供体细胞的持久性。
用200mg/kg CY清除同种异体抗原致敏的淋巴细胞，可使未照射小鼠的同种异体BM实现稳定的无移植物抗宿主病（GVHD）植入，而仅用相同剂量CY进行免疫抑制治疗则导致BM排斥。在用供体BM预处理前进行低剂量照射，可使诱导耐受的CY剂量降至100mg/kg。用降低剂量的CY进行同种异体抗原致敏淋巴细胞清除（APLD），与单独用照射和CY治疗相比，在显著更低的照射剂量后即可实现供体BM的植入。
我们的结果表明，专注于APLD的预处理比用CY和放射治疗进行全身免疫抑制具有明显优势。
