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Biomedical subjects

M Awwad

Publications and source records attributed to M Awwad.

6 recordsLinked to original sources
PubMed1990

Radiosensitive barrier to T-cell-mediated adoptive immunotherapy of established tumors.

This study shows that it is not possible to cause regression of the immunogenic SA-1 sarcoma by adoptive immunotherapy with tumor-sensitized T-cells, unless the tumor-bearing recipient is exposed to a sublethal dose of gamma-irradiation to remove a barrier that prevents adoptive immunity from being expressed. This barrier to adoptive immunotherapy was found to be regenerated between 2 and 4 weeks following irradiation, and its regeneration was associated with general repopulation of host T-cells. However, it was not regenerated in the absence of the thymus, thus showing that it is T-cell dependent. Evidence that it is caused by the presence of CD4+ suppressor T-cells was shown by the finding that it can be removed by depleting mice of CD4+ T-cells with anti-L3T4 monoclonal antibodies, but not by depleting them of CD8+ T-cells with anti-Lyt-2 monoclonal antibodies. Again, the barrier could be restored to irradiated recipients by infusing them with CD4+ T-cells, but not with CD8+ T-cells, from tumor-bearing donors. The barrier to adoptive immunotherapy was found to be tumor induced and to be paradoxically generated in concert with host concomitant immunity.

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PubMed1990

Elimination of cycling CD4+ suppressor T cells with an anti-mitotic drug releases non-cycling CD8+ T cells to cause regression of an advanced lymphoma.

This paper describes a model of successful immunotherapy of advanced lymphoma based on the selective elimination of cycling tumour-induced suppressor T cells. It shows that a single injection of the anti-mitotic drug, vinblasting (Vb), results in complete regression of a large L5178Y lymphoma and its metastases, but not if it is growing in an immunocompetent host. Vb-induced, immunologically mediated tumour regression was dependent on the anti-tumour function of CD8+ T cells, because regression was prevented by depleting the host of this subset of T cells 24 hr after Vb was given. Regression was also prevented by infusing the host with Vb-sensitive, CD4+ T cells from a tumour-bearing donor. These and other results are in keeping with the interpretation that Vb-induced regression of the L5178Y lymphoma depends on the ability of the drug to eliminate CD4+ suppressor T cells that are replicating, and to spare non-replicating CD8+ effector cells. It is suggested that at an advanced stage of growth of the L5178Y lymphoma the host possesses an acquired population of antigen-primed CD8+ effector T cells that are unable to become activated in response to abundant tumour antigen because of the dominant influence of CD4+ suppressor cells. Activation of these CD8+ T cells was indicated by the finding that they were rapidly converted from being cyclophosphamide (Cy) resistant to being highly Cy sensitive within 48 hr of giving Vb.

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PubMed1989

Elimination of CD4+ suppressor T cells from susceptible BALB/c mice releases CD8+ T lymphocytes to mediate protective immunity against Leishmania.

This study examined the capacity of BALB/c mice that had been depleted of T cell subpopulations to generate a protective immune response to Leishmania major. Thymectomized mice were depleted of either L3T4+ (CD4+) T lymphocytes, Ly2+ (CD8+) T lymphocytes, or both, by treatment with appropriate mAbs. It was found that susceptible mice were rendered resistant to Leishmania by an intravenous infusion of anti-L3T4 mAb. These mice generated an immune response that destroyed the parasite in the primary lesion and in visceral metastatic foci. CD4+ cell-depleted mice also acquired a capacity to mount a sustained delayed-type hypersensitivity (DTH) response to parasite antigens, indicating that DTH, per se, is not a disease-promoting mechanism in the susceptible murine host as has been suggested. Depleting BALB/c mice of CD8+, as well as CD4+ T cells, left them highly susceptible to Leishmania infection, thereby indicating that CD8+ lymphocytes are key protective cells. Our results can be interpreted as showing that the susceptibility of BALB/c mice is due to the generation of CD4+ cells that suppress either the generation or expression of CD8+ T cell-mediated antiLeishmania immunity.

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PubMed1989

Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells.

It was shown that it is possible to use cyclophosphamide (Cy) to cause immunologically mediated regression of the immunogenic, Cy-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice. In order to cause tumor regression it was necessary to give Cy shortly before or shortly after tumor implantation. However, regardless of whether Cy was given before or after tumor implantation, tumor regression did not commence until 10 days of progressive tumor growth, by which time the tumor was 1 cm in diameter. Tumor regression was associated with the presence in the spleen of an increased number of Lyt-2+ T-cells capable of passively transferring immunity to tumor-bearing recipients. This augmented level of immunity was sustained throughout the period of tumor regression. In contrast, a lower level of concomitant immunity generated by control tumor bearers decayed after Day 12 of tumor growth. Because the therapeutic effect of Cy could be inhibited by passive transfer of L3T4+ T-cells from normal donor mice it is apparent that the therapeutic effect of Cy is based on its ability to preferentially destroy L3T4+ suppressor T-cells. These putative precursor suppressor T-cells were regenerated 4 days after being destroyed by Cy. Taken together the results represent a striking example of the negative regulatory influence of suppressor T-cells on the immune response to an immunogenic tumor.

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