mediating the donor engraftment – promoting effect of local irradiation in an Ly - 5 congenic bone marrow transplant combination

Ito and coworkers1 describe a model where local irradiation enhances engraftment of CD45 congenic donor bone marrow cells. Their explanation is that the irradiated marrow sites produce cytokines that help proliferation of locally homed stem cells and initiate migration of stem cells to other, nonirradiated sites. This idea sounds appealing because administration of such cytokines would be an ideal opportunity to improve engraftment of transplanted stem cells. However, most of Ito et al’s results can be explained by additional immune suppression and/or additional ablation of the endogenous stem cell reserve. As published and referenced by the authors, an immune response against the CD45 antigen can influence engraftment of transplanted stem cells, especially when mild conditioning regimens are used,2 as was the case in the study by Ito and coworkers. An alternative transplant model using an intracellular marker (glucose-phosphate-isomerase) showed much higher levels of chimerism suggestive for alloreactivity against CD45. The allotype of CD45 serves as a minor antigen but this alloreactivity is very weak and does not prevent the coexistence of 2 stem cell populations (mixed chimerism), even under conditions of incomplete immune suppression. Ito et al claim that the high marrow dose might overcome immune resistance, but at 25% (5 107) of the dose they used, resistance was still evident in this model.2 Mediastinal irradiation (including the thymus) as employed by the authors was shown to be effectively immunesuppressing an alloresponse,3 which will result in higher levels of chimerism. Although thymectomy did not prevent the increase in chimerism, it seems probable that this procedure already resulted in less alloreactivity. Unfortunately, the authors do not present proper control data on chimerism levels in thymectomized mice without mediastinal irradiation. The alternative method using local irradiation of hind limbs also led to higher levels of chimerism.1 In that case, approximately 20% of the total marrow mass was irradiated4 and severely depleted of stem cells. This will most certainly provide additional marrow ablation, allowing engraftment of transplanted cells into these marrow sites. When this extra 20% is added to the 20% already achieved without local irradiation, a level of 40% chimerism might be expected, very close to the levels found in nonirradiated bones. Therefore, although cytokine production by irradiated bone marrow may explain the results presented by Ito and coworkers, alternative explanations such as those discussed here cannot be excluded unless other models without immune reactivity are used. The results show that engraftment depends on a delicate balance among immune suppression, stem cell ablation, and competition.