thymosin and Lymphoma--T-Cell

It was been previously reported that thyalpha1 can be used to activate monocytes, BMDM and TAM. However, the effect of thyalpha1 on other tissue macrophages has not been investigated. Moreover, there is no report about the use of thyalpha1-treated macrophages in adoptive immunotherapy of cancer. In view of these observations in the present study, we checked the response of various tissue macrophages to thyalpha1 for activation. Tissue macrophages showed differential response to thyalpha1; moreover, adoptive transfer of peritoneal macrophages treated with thyalpha1 to mice bearing spontaneous T-cell lymphoma designated as Dalton's lymphoma (DL) resulted in the prolongation of the survival time of tumor-bearing mice. The mechanism of macrophage therapy-dependent tumor regression was enhanced antitumor activity of macrophages in response to thyalpha1 treatment via their production of macrophage-activating cytokines that act in autocrine manner. These results will help in the development of immunotherapy against tumor based on activation of macrophage with thyalpha1.

Topics: Adjuvants, Immunologic; Animals; Immunotherapy, Adoptive; Lymphoma, T-Cell; Macrophage Activation; Macrophages, Peritoneal; Male; Mice; Mice, Inbred BALB C; Thymalfasin; Thymosin

The present investigation was conducted to study the effect of thymic peptide: thymosinalpha1 (thyalpha1) on the activation of tumor associated mphi (TAM) obtained from mice bearing a transplantable T cell lymphoma of spontaneous origin designated as Dalton's lymphoma, to produce nitric oxide (NO). It was found that in vivo administration of aqueous thymic extract obtained from thymus of normal mice or thyalpha1 could activate the TAM to produce enhanced amount of NO which was further augmented on in vivo treatment of these TAM by LPS. These observations suggest that thyalpha1 could prime TAM for activation by second signal of LPS. The study also presents evidence that tumor cell elaborate factors that enhance the effect of thyalpha1 on TAM for production of NO. This is the first study to show that thyalpha1 can activate TAM directly even in the absence of LPS, and may, therefore, have clinical significance.

Topics: Animals; Female; Lipopolysaccharides; Lymphoma, T-Cell; Macrophage Activation; Macrophages; Male; Mice; Nitric Oxide; Thymalfasin; Thymosin

In continuation with the earlier and ongoing studies on Thymosin-alpha-1 (Talpha1) exerting its immunomodulatory effects on various components of the immune system including T-cells, NK-cells, blood lymphocytes and macrophages, the role of Talpha1 in normal bone-marrow haematopoiesis has been investigated in the present study. The haematopoietic alterations associated with the growth of murine T-cell lymphoma, Dalton's Lymphoma (DL) and subsequently its restoration by Talpha1 was also investigated. It is observed that the non-adherent bone-marrow cells from normal mice (N-BMCs) exhibited enhanced proliferation on in vitro treatment with Talpha1 (dose range of 1-100 ng/ml) with maximal response at 100 ng/ml of Talpha1. In vitro stimulation with 100 ng/ml of Talpha1 also resulted in increased myeloid colony formation, as manifested by the rise in total number of colonies, frequency of the individual colony types and their size. This response was further upregulated in the presence of various colony stimulating factors (CSFs) like MCSF, GMCSF, GCSF and IL-3. Similarly, in vivo administration of Talpha1 (a single intraperitoneal injection of 10 microg per mouse) to normal mice also resulted in enhanced proliferation and colony formation by BMCs as compared with BMCs obtained from untreated mice. On the contrary, the progressive growth of T-cell lymphoma in mice led to suppressed myelogenesis, with marked reduction in the total colony numbers and their size. The BMCs from DL-bearing mice (DL-BMCs) displayed a preferential lineage-restricted differentiation towards the granulocytic-type colonies with maximum numbers of CFU-Gs and CFU-GMs, followed by CFU-Ms. However, incubation of DL-BMCs with 100 ng/ml of Talpha1, in vitro restored their suppressed proliferation and colony forming ability (CFA) with significantly enhanced total number of colonies and individual colony types, which further increased in the presence of CSFs. In vivo studies with BMCs from DL-bearing mice treated with single intraperitoneal injection of 10 microg Talpha1/mouse also resulted in significant enhancement in their proliferative as well as colony forming ability in comparison to that of untreated DL-mice. The present observations suggest that Talpha1 can positively modulate the haematopoietic functions of normal murine BMCs, in addition to its myelorestorative role in tumour-bearing mice showing suppressed myelopoiesis.

Topics: Animals; Bone Marrow; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Interferon-gamma; Interleukin-1; Interleukin-10; Lymphoma, T-Cell; Mice; Mice, Inbred BALB C; Myelopoiesis; RNA, Messenger; Thymalfasin; Thymosin; Tumor Necrosis Factor-alpha

The observations presented in this paper indicate that serum of Dalton's lymphoma (DL) bearing mice contained certain soluble factor(s) that augmented the induction of apoptosis in thymocytes in a time- and dose-dependent manner. DL-ascitic fluid and DL-conditioned medium could also induce apoptosis of thymocytes in vitro, though the magnitude of the same was consistently lower than that induced by serum of DL-bearing mice. It was observed that the interaction of FasL and TNFalpha with their respective receptors could trigger apoptosis in thymocytes. Elucidation of the signal transduction mechanism revealed involvement of protein tyrosine kinase, protein kinase C and ser/thr phosphatases with concomitant increase in the level of protein products of apoptosis associated genes p53, bax, bad, fas and fas ligand and cleavage of N-terminal 23 kDa fragment of Bcl-2 that exhibited Bax-like death effector properties. Further, we report, for the first time, the ability of thymosin alpha-1, an immunopotentiating thymic hormone, to antagonize apoptosis in thymocytes induced by factors present in serum of DL-bearing mice. The underlying mechanism of tumor serum induced apoptosis inhibition by thymosin alpha-1 was also analyzed. The signal transduction cascade evoked by thymosin alpha-1 involves activation of protein kinase C with a decrease in the level of protein products of proapoptotic genes like bax and bad and increase in the protein products of bcl-2 gene.

Topics: Animals; Apoptosis; Calcium; Culture Media, Conditioned; Female; Gallic Acid; Lymphoma, T-Cell; Male; Mice; Mice, Inbred BALB C; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; T-Lymphocytes; Thymalfasin; Thymosin; Tumor Suppressor Protein p53