Slavin Shimon
Dept of Bone Marrow Transplantation & Cancer Immunotherapy, Hadassah University Hospital, Jerusalem, Israel.
Int J Hematol. 2002 Aug;76 Suppl 1:172-5. doi: 10.1007/BF03165240.
Bone marrow transplantation (BMT) which represents an important clinical tool for treatment of patients with a wide variety of malignant and non-malignant diseases, however, the procedure is associated with procedure-related toxicity and mortality as well as unavoidable late complications. Many of the undesirable consequences of BMT are caused directly or indirectly by the intensive conditioning administered during the pre-transplant period. However, if the main goal of the BMT procedure is to enable immunotherapy by alloreactive donor lymphocytes, the conditioning prior to BMT needs to be reconsidered, because transplantation tolerance across major histocompatibility complex (MHC) occurs spontaneously in nature, as evidenced by the fact that pregnant females do not reject their conceptus. In fact, as shown by Owens in the 1940s, placental parabiosis in utero leads to permanent mixed chimerism and bilateral transplantation tolerance. These observations followed by experiments carried out in the 1950s by Billingham et al. suggested that infusion of parental stem cells into neonates with no exogenous immunosuppressive treatment resulted in mixed chimerism and permanent transplantation tolerance to donor alloantigens. Thus, a window of opportunity provided shortly after delivery, was sufficient for induction of tolerance without the need for heavy conditioning. Tolerant recipients were shown to be chimeras with only a small proportion of donor cells. However, without corroborating evidence that transplantation tolerance could be intentionally induced, the approach could not be applied in clinical practice for immunocompetent recipients. Starting in 70s, we documented the feasibility of establishing bilateral transplantation tolerance by mixed chimerism following non-myeloablative conditioning in immu. nologically mature recipients across MHC in mice, rats and dogs. Several studies have shown that reduced intensity conditioning can be very useful for immunoregulation whereas more intensive the pre-grafting immunosuppression resulted in more aggressive the GVHD. These and other findings suggested that lower intensity conditioning may be sufficient for engraftment of donor stem cells, thus suggesting that immunosuppression without myeloablation may be sufficient for prevention of allograft rejection. Following engraftment of donor stem cells, donor lymphocytes infused with bone marrow or mobilized blood stem cells can eradicate residual hematopoietic cells of host origin, occasionally non-hematopoietic tumor cells of host origin as well. Whenever indicated, donor lymphocytes infusion (DLI) can be used at a later stage post BMT to eradicate residual malignant cells of host origin or for the treatment of residual or recurrent disease. Taken together, ongoing clinical studies suggest that high-dose, myeloablative chemoradiotherapy, could be safely replaced with non-myeloablative conditioning (NST).
骨髓移植（BMT）是治疗多种恶性和非恶性疾病患者的重要临床手段，然而，该手术会带来与手术相关的毒性和死亡率以及不可避免的晚期并发症。BMT的许多不良后果直接或间接由移植前期进行的强化预处理导致。然而，如果BMT手术的主要目标是通过同种异体反应性供体淋巴细胞实现免疫治疗，那么BMT前的预处理就需要重新考虑，因为在自然界中主要组织相容性复合体（MHC）的移植耐受性是自发产生的，怀孕女性不会排斥其胎儿这一事实就证明了这一点。事实上，正如欧文斯在20世纪40年代所表明的，子宫内胎盘联体共生会导致永久性混合嵌合体和双侧移植耐受性。随后在20世纪50年代由比林厄姆等人进行的实验表明，在没有外源性免疫抑制治疗的情况下，将亲代干细胞输注到新生儿体内会导致混合嵌合体以及对供体同种异体抗原的永久性移植耐受性。因此，出生后不久提供的这个机会窗口足以诱导耐受性，而无需进行高强度预处理。耐受性受体被证明是仅含有一小部分供体细胞的嵌合体。然而，由于没有确凿证据表明可以有意诱导移植耐受性，这种方法无法应用于有免疫能力受体的临床实践。从20世纪70年代开始，我们记录了在小鼠、大鼠和犬等免疫成熟受体中，通过非清髓性预处理后的混合嵌合体建立双侧移植耐受性的可行性。多项研究表明，降低强度的预处理对免疫调节非常有用，而移植前更强的免疫抑制会导致更严重的移植物抗宿主病（GVHD）。这些以及其他发现表明，较低强度的预处理可能足以使供体干细胞植入，因此表明无骨髓消融的免疫抑制可能足以预防同种异体移植排斥。在供体干细胞植入后，与骨髓或动员的血液干细胞一起输注的供体淋巴细胞可以清除宿主来源的残留造血细胞，偶尔也可以清除宿主来源的非造血肿瘤细胞。在任何需要的时候，供体淋巴细胞输注（DLI）可以在BMT后的后期用于清除宿主来源的残留恶性细胞或治疗残留或复发性疾病。综上所述，正在进行的临床研究表明，高剂量、清髓性放化疗可以安全地被非清髓性预处理（NST）取代。
