Successful bone marrow transplantation across major histocompatibility barriers in rhesus monkeys

Limited donor availability precludes that improved tissue typing will contribute to a more general application of bone marrow transplantation in man. We have therefore analyzed other modifying factors influencing acceptance of a bone marrow graft and the resulting GVH reaction, and have shown in an outbred species that their judicious application permits successful bone marrow transplantation across MHC barriers. Acceptance of a graft is described as a balance between the graft's immune reactivity (GVH reaction) and the immune reactivity of the host that escapes the conditioning regimen (HVG reaction). This concept leads to the conclusion that the removal of immunocompetent lymphocytes from the graft, required to control the GVH reaction, requires a more effective conditioning regimen. Such a regimen, allowing for take of low numbers of histoincompatible stem cell concentrates, may consist of TBI in two large fractions, given several days apart. In order to decrease the risks of late radiation damage, refined versions of this regimen have to be designed for application in man, although the present conditioning regimen of 2 fractions of 700 cGy x-rays, given 3 days apart, is very well tolerated by monkeys. Lethal GVH reactions can be prevented if the graft is depleted from immunocompetent lymphocytes and the recipient subjected to gastrointestinal decontamination. This confirms and extends earlier studies in mice and opens the prospect of the use of other than MHC-identical sibling donors in man. Recontaminated monkeys survived as stable chimeras, and their immune reconstitution, investigated in a small number, seems to result in near-normal immune functions. Application in man of selective elimination of lymphocytes from the graft suffers from uncertainty regarding the number of stem cells required for lasting takes with current conditioning regimens. However, the estimate reached in histoincompatible monkeys, compared with the 50% autologous bone marrow rescue doses in various species, suggests that the number of cells presently employed for allogeneic unfractionated bone marrow transplantation in man yields sufficient numbers of stem cells.