Toshiaki Takayanagi

A Mathematical Analysis of the Interactions between Immunogenic Tumor Cells and Cytotoxic T Lymphocytes

Recent developments of biotechnology have enabled us to use immunotherapy against certain kinds of tumors in patients. However, it is reasonable to doubt if the immunotherapy can completely aid the rejection of tumors that have escaped from the immune system. In this paper, we propose a new mathematical model of tumor immunity by tumor‐specific cytotoxic T lymphocytes (CTLs), since tumor‐specific CTLs play an important role in tumor immunity. Using this model, we have mathematically investigated the interactions between immunogenic tumor cells (TCs) and tumor‐specific CTLs and evaluated the availability of immunotherapies for tumors. The findings herein demonstrate that three kinds of dynamics of tumor immunity exist: i.e. (1) TCs continue to proliferate with CTLs; (2) TCs are rejected by CTLs; and (3) TCs equilibrate with CTLs, but with little possibility of the equilibrium. The findings also demonstrate that a sufficient increase in CTLs by immunotherapy can aid the rejection of TCs, but an insufficient increase in CTLs by immunotherapy causes only a transient regression of TCs. Clinically the findings mean that increasing tumor‐specific CTLs, e.g., by vaccination or adoptive transfer of tumor‐specific CTLs expanded ex vivo, can theoretically aid the rejection of TCs.

Effects of non-major histocompatibility antigens on acute graft-versus- host reaction after allogeneic bone marrow transplantation

In the present study using an experimental BMT system we analyzed the effects of disparity at non-MHC Ag including minor lymphocyte stimulatory-1a (Mls-1a) Ag on the acute GVH reaction (GVHR) induced by MHC class I Ag. Mismatch at MHC (class I) Ag alone did not induce clinically detectable acute GVHR in this model. However, BMT mice prepared with a combination of both class I and non-MHC Ag mismatches showed signs of clinical GVHR and various cytokines were produced by the spleen cells at an early stage (4 days) after BMT. Although no clinical GVHR was detected in BMT chimeras prepared with a non-MHC mismatched but MHC matched combination, large amounts of various cytokines were secreted by spleen cells. Cytokine production in the latter two kinds of chimeras paralleled the increase of Mls-1a reactive Vβ 6+ T cells in the host spleen. Marked cytokine production induced by Mls-1a Ag was confirmed by MLR. Thus, these cytokines appeared to be produced by T cells responding to Mls-1a (ie Vβ 6+ T cells) and to augment the T cell responses to MHC class I which resulted in clinically detectable GVHR in chimeras prepared with the combination mismatched at both MHC class I and non-MHC loci.

Delayed Clearance of Zymosan-induced Granuloma and Depressed Phagocytosis of Macrophages with Concomitant Up-regulated Kinase Activities of Src-family in a Human Monocyte ChemoaHractant Protein-1 Transgenic Mouse

A human monocyte chemoattractant protein-1 (hMCP-1) transgenic mouse (Tgm) line which constitutively produces a large amount of hMCP-1 (7-13 ng/ml in the serum) was established. Although expression of the transgene was detected in various tissues, an accumulation of macrophages (Mphi) was seen in only lymphoid organs which might be attributed to the high concentration of hMCP-1 in these organs. A reduced phagocytosis by peritoneal Mphi in vivo and a delayed clearance of granulomas in the liver following zymosan administration were observed in these Tgm. However, peritoneal exudate cells (PEC) from Tgm exhibited normal in vitro phagocytic activity and nitric oxide (NO) production upon stimulation with IFN-gamma as compared with those from non-Tgm. In addition, high activities of src-family protein tyrosine kinases (PTK), Fgr and Hck, were also noted in the peritoneal resident cells from Tgm, whereas the level of mitogen-activated protein kinase (MAPK) activity was almost the same as that of non-Tgm. It was suggested that the low functional activities of Tgm Mphi seen in vivo were attributed to down-regulation of the unique transducing system of hMCP-1 signals under the influence of a high concentration of the hMCP-1. It seemed that the depressed functions were recovered when the peritoneal cells were released ex vivo from such a high hMCP-1 environment.

Influence of graft versus host reaction on the T cell repertoire differentiating from bone marrow precursors following allogeneic bone marrow transplantation

When lethally irradiated AKR (Mls-1a) mice were reconstituted with bone marrow (BM) cells plus a small number (0.5%) of mature T cells from allogeneic B10.AQR or B10 (Mls-1b) mice and minor GVHR was induced in the recipients, almost complete donor chimerism was accomplished in the early stages after reconstitution. By contrast, in irradiated AKR mice reconstituted with T cell-depleted BM cells alone from B10 or B10.AQR mice, radio-resistant T cells of recipient origin persisted for a relatively long period in peripheral lymphoid tissues. In this paper the influence of residual T cells in the chimeric mice on generation of the T cell repertoire derived from donor BM is discussed. It will be demonstrated that the recipient (AKR) T cells are capable of producing Mls-1a antigens (Ag) after lethal irradiation in vivo. These recipient T cells eventually induce clonal elimination of Mls-1a reactive V beta 6+, V beta 8.1+ and V beta 9+ T cells derived from developing thymocytes of donor BM origin. The Mls-1a reactive T cells are not eliminated in GVHR chimeras in which recipient T cells are absent. However, V beta 5+ T cells reactive to I-E plus Etc-1 Ag are deleted in the chimeras undergoing GVHR. These results indicate that recipient cells which produce tissue-specific antigens (tolerogens) should be taken into consideration when generation of the T cell repertoire of donor origin following allogeneic BM transplantation is investigated.

Computer Simulations of Slow Progression of Human Immunodeficiency Virus Infection and Relapse during Anti-HIV Treatment with Reverse Transcriptase Inhibitors and Protease Inhibitors

Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have been very serious problems since the 1980s. The progression of HIV infection into AIDS can be suppressed to some extent with reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs); however, there are some serious problems with treatments using the anti‐HIV drugs (e.g. very high expense, complicated administration, and drug resistance). Hence, more studies on HIV and the development of more effective anti‐HIV treatments are required. We consider it important to understand the complex dynamics involved in HIV infection, and we therefore propose new mathematical models of HIV infection. In the modeling, we have paid attention to the nonlinear relations between stimuli and responses (i.e., when responses are plotted against the logarithm of stimuli, a sigmoid curve is obtained), and to lymphoid organs which seem more important than the blood compartment (i.e., lymphoid organs are major reservoirs of HIV virions and contain most of the lymphocytes). Using the models, we have found that viral antigenic mutation plays an important role in the slow progression in the chronic phase of HIV infection. We have also found that viral antigenic mutation can cause relapse of HIV infection when the inhibition rate of anti‐HIV drugs is low and that viral antigenic mutation cannot cause relapse when the inhibition rate is high.

Simulations of human immunodeficiency virus infection

Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have been very important problems all over the world. The progression of HIV infection into AIDS is controlled with anti-HIV drugs, but the treatments with the anti-HIV drugs have some problems. Hence, the research and development of more effective anti-HIV treatments have been performed. As we consider it important to understand the dynamics of HIV infection, we propose a new mathematical model of HIV infection. The model is characterized by the calculations of responses against stimuli; that is, the experimental phenomena (when the values of responses are plotted against the logarithm of the values of stimuli, a sigmoid curve is obtained) are incorporated into the model. By using the calculations of the model, we obtain the simulation results which show a slow increase in the viral load and a slow decrease in non-infected CD4/sup +/ T cells after the acute phase.

Acute Graft Versus Host Reaction (GVHR) Against Major / Minor Histocompatibility Antigens

When irradiated minor lymphocyte stimulatory-la (Mls-1a) mice were reconstituted with bone marrow cells plus mature T cells from Mls-lb and H-2 class I incompatible mice, acute GVHR was induced in the recipients. Majority of responding cells were shown to be CD4+Vs6+ T cells derived from donor mature T cells. It appeared that Mls-la antigen (Ag) was a major target Ag. However, when Mls-lb donor and Mls-la recipient mice were H-2 matched, the severity of GVHR was mar-kedly reduced. Thus, disparity at the Mls-l locus alone appeared not to be sufficient to induce dete-ctable GVHR. In mixed lymphocyte reaction (MLR), T cell proliferation against Mls-1a plus H-2 class I Ag was as high as that against H-2 class I Ag alone. On the other hand, production of IL-2, IL-4 and TNF-α by the T cells responding to H-2 class I plus Mls-1aAg was considerably greater than that by T cells responding to class I Ag alone. The present findings suggest that CD4+Vs6+ T cells responding to Mls-laAg and producing IL-2, IL-4 and TNF-α play a significant role, which may result in augmentation of allo-responses to the host H-2 class I Ag and substantial GVHR.