The in vivo biological activity of IL-2 can be dramatically increased by complexing with anti-IL-2 mAb. Moreover, IL-2/anti-IL-2 mAb immunocomplexes selectively stimulate different subsets of immune cells, depending on the clone of anti-IL-2 mAb that is used. Thus, IL-2/S4B6 mAb complexes strongly stimulate CD122high populations, namely NK and memory CD8+ T cells. They also intermediately stimulate Treg cells. Conversely, IL-2/JES6.1 mAb immunocomplexes have no stimulatory activity for CD122high populations. However, they potently and highly selectively stimulate CD25+ cells (i.e., Treg and activated T cells). IL-2/S4B6 mAb immunocomplexes have also been shown to possess antitumor activity in various mouse tumor models.

• Keywords
• Anti-IL-2 mAb, IL-2, cancer immunotherapy, immunocomplexes, selective stimulatory activity,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Experiments were designed to examine whether local cytokine therapy of subcutaneous (s.c.) tumours results in inhibition of their lung metastases. Moderately immunogenic, major histocompatibility complex (MHC) class I and II negative. B7 negative, metastasizing murine carcinoma MK16 transplantable in syngeneic mice was obtained by co-transfection of human papilloma virus type 16 (HPV 16) E6/E7 and activated H-ras oncogene plasmid DNA into C57BL/6 kidney cells. After s.c. transplantation of the malignantly converted MK16 cells, the majority of the transplanted mice developed lung metastases; the number and size of the lung metastases increased with the increasing size of the s.c. tumour. Therapy of 5-day MK16 tumours by peritumoral administration of recombinant interleukin-2 (IL-2) and recombinant interleukin-12 (IL-12) inhibited growth of the s.c. MK16 tumour transplants and reduced the number of MK16 lung metastases. To investigate the antimetastatic effect of IL-2 and IL- 12 in a clinically more relevant setting, surgical minimal residual tumour disease was utilized. Subcutaneously growing MK16 carcinomas, 8-12 mm in diameter, were removed on day 30 and the operated mice were injected with IL-2 or IL- 12 on days 35-39 and 42-46 at the site of the operation. Treatment with IL-2 significantly reduced the percentage of MK16 tumour recurrences as well as the number of lung metastases, whereas the effect of IL- 12 was substantially weaker and statistically insignificant.

• MeSH
• B7-1 Antigen metabolism   MeSH
• B7-2 Antigen MeSH
• Cell Division drug effects   MeSH
• Antigens, CD metabolism   MeSH
• Histocompatibility Antigens metabolism   MeSH
• Tumor Virus Infections drug therapy   pathology   MeSH
• Papillomavirus Infections drug therapy   pathology   MeSH
• Interleukin-12 therapeutic use   MeSH
• Interleukin-2 therapeutic use   MeSH
• Carcinoma drug therapy   secondary   virology   MeSH
• Membrane Glycoproteins metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Lung Neoplasms drug therapy   secondary   MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Cell Line, Transformed MeSH
• Neoplasm Transplantation MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• B7-1 Antigen MeSH
• B7-2 Antigen MeSH
• Antigens, CD MeSH
• Cd86 protein, mouse MeSH Browser
• Histocompatibility Antigens MeSH
• Interleukin-12 MeSH
• Interleukin-2 MeSH
• Membrane Glycoproteins MeSH
• Antineoplastic Agents MeSH

The inbred strain STS/A exhibits a higher proliferative response in the mixed lymphocyte culture (MLC) to stimulator cells of all 11 tested inbred mouse strains with 10 different major histocompatibility complex (MHC) haplotypes, as well as to stimulation with IL-2 than does the strain BALB/cHeA. However, alloantigen-stimulated BALB/c cells produce more IL-2 than STS/A cells. To study the genetic basis of these differences, we used 20 recombinant congenic strains (RCS) of the CcS/Dem series. Each of these CcS/Dem RC strains contains a different subset of about 12.5% of genes from the STS/A strain and the remaining approximately 87.5% of BALB/c origin genes. As a result the multiple non-linked genes responsible for phenotypic differences between BALB/c and STS/A became separated into different CcS/Dem strains. The strain distribution pattern (SD) of high or low MLC response of individual CcS/Dem strains to stimulator cells of four different strains was almost identical, indicating that differences in responsiveness, rather than the alloantigenic difference itself, determine the magnitude of the response, and that the responsiveness to different alloantigens is largely controlled by the same genes. The SDP of IL-2 stimulation was different from that of MLC responsiveness. The differences in the proliferative responses observed among individual CcS/Dem strains were not due to differences in numbers of CD3+, CD4+ or CD8+ cells or to the observed differences in IL-2 production, and hence they likely reflect genetically determined intrinsic properties of T cells. These results show that a set of non-linked genes controls proliferative responses in MLC irrespective of the MHC haplotype of the stimulator cells, and that stimulation with IL-2 and production of IL-2 are controlled by different subsets of genes. Since the genomes of all RCS are extensively characterized by microsatellite markers, they can be used to map the genes controlling proliferative responsiveness to stimulation with alloantigens and IL-2.

• MeSH
• Lymphocyte Activation * MeSH
• CD3 Complex immunology   MeSH
• CD4-Positive T-Lymphocytes immunology   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Major Histocompatibility Complex MeSH
• Interferon-gamma physiology   MeSH
• Interleukin-10 physiology   MeSH
• Interleukin-2 pharmacology   MeSH
• Cells, Cultured MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Spleen cytology   MeSH
• T-Lymphocyte Subsets immunology   MeSH
• Lymphocyte Culture Test, Mixed MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CD3 Complex MeSH
• Interferon-gamma MeSH
• Interleukin-10 MeSH
• Interleukin-2 MeSH

T lymphocytes of the strain BALB/cHeA exhibit a low proliferative response to IL-2 and a high response to the anti-CD3 monoclonal antibodies, while the strain STS/A lymphocyte response to these stimuli is the opposite. We analyzed the genetic basis of this strain difference, using a novel genetic tool: the recombinant congenic strains (RCS). Twenty BALB/c-c-STS/Dem (CcS/Dem) RCS were used, each containing a different random set of approximately 12.5% of the genes from STS and the remainder from BALB/c. Consequently, the genes participating in the multigenic control of a phenotypic difference between BALB/c and STS become separated into different CcS strains where they can be studied individually. The strain distribution patterns of the proliferative responses to IL-2 and anti-CD3 in the CcS strains are different, showing that different genes are involved. The large differences between individual CcS strains in response to IL-2 or anti-CD3 indicate that both reactions are controlled by a limited number of genes with a relatively large effect. The high proliferative response to IL-2 is a dominant characteristic. It is not caused by a larger major cell subset size, nor by a higher level of IL-2R expression. The response to anti-CD3 is known to be controlled by polymorphism in Fc gamma receptor 2 (Fcgr2) and the CcS strains carrying the low responder Fcgr2 allele indeed responded weakly. However, as these strains do respond to immobilized anti-CD3, while the STS strain does not, and as some CcS strains with the BALB/c allele of Fcgr2 are also low responders, additional gene(s) of the STS strain strongly depress the anti-CD3 response. In a backcross between the high responder and the low responder strains CcS-9 and CcS-11, one of these unknown genes was mapped to the chromosome 10 near D10Mit14. The CcS mouse strains which carry the STS alleles of genes controlling the proliferative response to IL-2 and anti-CD3 allow the future mapping, cloning, and functional analysis of these genes and the study of their biological effects in vivo.

• MeSH
• Lymphocyte Activation * MeSH
• CD3 Complex immunology   MeSH
• Species Specificity MeSH
• Interleukin-2 pharmacology   MeSH
• Chromosome Mapping MeSH
• Antibodies, Monoclonal immunology   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Flow Cytometry MeSH
• Recombination, Genetic MeSH
• T-Lymphocytes immunology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CD3 Complex MeSH
• Interleukin-2 MeSH
• Antibodies, Monoclonal MeSH

Immunobiological activity of the polybacterial lysate Olimunostim (P. acnes, K. pneumoniae, S. aureus) was examined by investigating its effects on murine lymphocytes. When added to in vitro lymphocyte cultures, Olimunostim induced interleukin-2 (IL-2) biological activity (in a 2-d culture) and subsequently potentiated lymphocyte proliferation (on day 3); the latter effect was dependent on the presence of adherent cells. In vivo, significant enhancement of lymphocyte reactivity to T-mitogens and increase of CD4+ helper-inducer T lymphocytes were observed 3 d after a subcutaneous application of Olimunostim to mice with cellular immune deficiency. These results confirm the modulatory properties of Olimunostim towards lymphocytes both in vitro and in vivo, which may form a basis for its clinical application.

• MeSH
• Adjuvants, Immunologic metabolism   pharmacology   MeSH
• Lymphocyte Activation MeSH
• Immunity, Cellular * MeSH
• Interleukin-2 biosynthesis   MeSH
• Klebsiella pneumoniae metabolism   MeSH
• Concanavalin A pharmacology   MeSH
• Lymphocytes immunology   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Propionibacterium acnes metabolism   MeSH
• Staphylococcus aureus metabolism   MeSH
• Immunologic Deficiency Syndromes immunology   therapy   MeSH
• T-Lymphocytes immunology   MeSH
• In Vitro Techniques MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adjuvants, Immunologic MeSH
• Interleukin-2 MeSH
• Concanavalin A MeSH

Our data demonstrate the granulopoietic toxicity of aflatoxin B1 (AFB1) in vivo and show an impact of this mycotoxin on the production of some humoral regulatory factors dealing with the granulopoietic developmental pathway (CSA, IL-1, IL-2). The dose of AFB1 studied represented approximately 1/5 of LD50 for young male rats. An early suppressive effect of AFB1 towards CFU-GM was transient in treated animals. The peak in granulopoietic activity was preceded in time by an increased CSA and IL-1 formation. Elevated IL-2 synthesis and increased T cell activation paralleled the peak in granulopoietic activity.

• MeSH
• Aflatoxin B1 toxicity   MeSH
• Colony-Forming Units Assay MeSH
• Bone Marrow Cells MeSH
• Cytokines biosynthesis   drug effects   MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor biosynthesis   MeSH
• Granulocytes drug effects   MeSH
• Interleukin-1 biosynthesis   MeSH
• Interleukin-2 biosynthesis   MeSH
• Bone Marrow drug effects   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Macrophages drug effects   metabolism   MeSH
• Rats, Inbred F344 MeSH
• Spleen cytology   drug effects   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aflatoxin B1 MeSH
• Cytokines MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor MeSH
• Interleukin-1 MeSH
• Interleukin-2 MeSH