Graft-vs-leukemia and moderation of graft-vs-host reaction in transplantation therapy of viral leukemia.

In transplantation studies of Rauscher leukemic SJL/J mice longer median survival times (MST) were obtained with spleen cells from syngeneic donors than with marrow. These could be further extended by immunization of the donors to Rauscher virus (RLV) and Rauscher leukemia cells. This suggests that spleen cells exert a greater graft-vs-leukemia effect than marrow. Nevertheless, with syngeneic cells all recipients eventually died of leukemia relapse. In contrast, the use of RLV-resistant C57BL/10J allogeneic marrow cells resulted in a substantial number of long-term survivors and a low incidence of GvH disease, while the use of pure allogeneic spleen cells resulted in early and fatal GvH response in all recipients. To determine if allogeneic spleen cells might have any demonstrably beneficial effect on survival of leukemic mice various small quantities of C57BL/10J spleen cells were mixed with marrow from the same donors and engrafted into normal and leukemic SJL/J recipients. Among the normal mice MST decreased as a function of spleen cell concentration. However, with the leukemics the use of 2.5 or 5% spleen cells resulted in later deaths than that found when leukemic mice were given only marrow. Also, for all allogeneic spleen/marrow mixtures tested, survival of leukemic recipients exceeded that of normal recipients given the same cell mixtures. These data suggest a possible beneficial effect of small amounts of allogeneic spleen cells in transplantation therapy for leukemia, and a possible competitive interaction of anti-host and anti-leukemic activities of the transplanted cells leading to a moderation of the GvH response.

Fatal response suggestive of graft-versus-host reaction following transplantation of spleen cells from allogeneic athymic (nude) donors.

Normal female SJL/J mice were exposed to 950 R of total body irradiation (TBI) and transplanted with allogeneic spleen or marrow cells from normal or nude (athymic) C57BL/10 donors. With nude mouse donor marrow, no evidence of graft-versus-host (GVH) response was seen and all SJL/J recipients survived for more than 75 days. In contrast, when spleen cells taken from the same nude C57BL/10 donors were engrafted into SJL/J mice the incidence of fatalities among the recipients was 70% by 60 days. Furthermore, all of the recipients of nude mouse spleen cells showed signs strongly suggestive of GVH response. Comparative fatalities among the recipients of cells from normal donors were 27% for marrow at 60 days and 100% for spleen at 11 days, and these were accompanied by the characteristic signs of GVH response usually seen after transplantation of cells from normal allogeneic donors. Transplantation of normal C57BL/10 marrow mixed with small numbers at normal spleen cells resulted in an increase in the number of fatalities among the SJL/J recipients, and an increase in the severity of the signs of GVH response as compared to that seen following engraftment of normal C57BL/10 marrow alone. However, no such increases in fatalities or severity were observed when similar amounts of nude C57BL/10 spleen cells were engrafted along with normal marrow cells into SJL/J recipients. The results suggest that a factor may exist in nude mouse spleen which in allogeneic transplantation can lead to a fatal response suggestive of GVH reaction, but that nude mouse spleen lacks the T cell-related ability to enhance GVH response that has been previously demonstrated following allogeneic transplantation using normal spleen and marrow donors.

Histocompatibility influence in allogeneic marrow transplantation therapy of murine viral leukemia. I.--Studies of the relative influence of major versus minor histocompatibility determinants.

The anti-leukemic effectiveness (GvL activity) and anti-host response (GvH response) of several allogeneic donor marrows were compared in lethally irradiated normal and Rauscher leukemia SJL/J recipients. Although both types of effects could be demonstrated, the degree of GvL activity did not parallel the severity of GvH response. The level of GvL activity of the donor marrow also appeared to be independent of sensitivity of the donors to the leukemia inducing Rauscher virus (RLV), as a high level of leukemia recurrence was found using marrow from RLV-resistant RF/J donors, while a lesser degree of recurrence occurred with the use of RLV-sensitive DBA-2J marrow. Analysis of the possible influence of major (MHC) and Minor (MiHL) histocompatibility loci suggested that GvL activity may be independent of the H-2 locus, and that the "a" alleles of the H-4 and H-13 loci may not be contributing to GvL effect. Likewise the "a" alleles of the H-7 and H-12 loci did not appear to affect the severity of GvH response. The possibly that GvL activity may be independent of th MHC, but governed by MiHL possibility different from those regulating GvH response might explain why in this and previous studies GvL activity could only be demonstrated following allogeneic marrow transplantation but did not appear to correlate with severity of GvH response.