Liu-ANS Nov 2002- J shaped Immune response Curve

Dose-effect relationship in the immune system after exposure to ionizing radiation

Shu-Zheng Liu

Immunology Laboratory

Radiobiology Research Unit, Ministry of Health, P.R.C.

At Jilin University Norman Bethune Medical Center

8 Xinmin Street, Changchun 130021, China

It is well known that immune surveillance is one of the most important defense mechanisms of the body against cancer and infection. Most carcinogens are immunosuppressants, and so is ionizing radiation, but only at medium to high doses. The stimulatory effect of low dose radiation (LDR) on immunity has been studied at molecular, cellular as well as organism levels [1-9]. But the dose-effect relationship of these changes, especially in a coordinated manner synthesizing various effects at different levels, has not been reported. In this presentation 52 immunologic parameters in two categories are pooled to construct dose-effect curves. The dose-effect relationship of one category consisting of 20 parameters which down-regulate immunity showed a J-shaped curve (left upper panel of figure 1), and that of the second category consisting of 32 parameters which up-regulate immunity showed an inverted J-shaped curve (right upper panel of figure 1). These curves were constructed each with 10~11 doses ranging from 0 to 10 Gy. It should be emphasized that in order to construct such “complete” curves 3~4 dose points in each section of 0.01~0.1 Gy, 0.1~1.0 Gy and 1.0~10.0 Gy within this whole dose range have to be chosen. In many studies in the literature doses below 0.2 Gy were often neglected, thus the effect of LDR would be missed. This is shown in the lower panels of figure 1 in which data with doses between 0.025 and 0.2 Gy were omitted, thus giving rise to quadratic curves instead of the J- or inverted J-shaped curves.

Figure 1. Dose-effect curves of composite immune parameters following exposure to X-rays

Left upper panel: J-shaped curve constructed from 20 parameters that down-regulate immune activity when stimulated; left lower panel: same as the left upper one from data with doses between 0.025 and 0.2 Gy omitted; right upper panel: inverted J-shaped curve constructed from 32 parameters that up-regulate immune activity when stimulated; right lower panel: same as the right upper one from data with doses between 0.025 and 0.2 Gy omitted.

Two examples are given in figure 2. The left upper panel in this figure shows the dose-effect relationship of cAMP concentration in thymocytes 24h after whole-body irradiation (WBI) of mice with X-rays. This J-shaped curve demonstrates that at doses within 0.2 Gy the cAMP concentration in the thymocytes is lowered and this lowering of cAMP concentration would lead to stimulation of immunity since the decreased concentration of cAMP (accompanied with increased cGMP concentration) would signal via down-regulated expression of its downstream molecule protein kinase A (PKA) to up-regulate the expression of transcriptional factors involved in induction of genes of immune responses while increase in cAMP (accompanied with decrease in cGMP) concentration in the thymocytes would lead to immune suppression [9,10]. The right upper panel of figure 2 shows the dose-response relationship of interferon-gamma (IFNg) secretion by mouse splenocytes 24h after WBI with X-rays [11]. This is an inverted J-shaped curve. When doses between 0.025 and 0.2 Gy are omitted, both the J-shaped and inverted J-shaped curves are converted to quadratic curves as shown respectively in the left and right lower panels of figure 2.

Figure 2. Dose-effect curves of individual immune parameters after exposure to X-rays

Left upper panel: J-shaped curve of cAMP concentration in mouse thymocytes 24h after WBI with X-rays; left lower panel: same as the left upper one from data with doses between 0.025 and 0.2 Gy omitted; right upper panel: inverted J-shaped curve of IFNg secretion by mouse splenocytes 24h after WBI with X-rays; right lower panel: same as the right upper one from data with doses between 0.025 and 0.2 Gy omitted.

Other parameters examined in the immune system, especially those of T lymphocytes, mostly show the same pattern of response to different doses of radiation. These include cellular functions, intercellular reactions with expression of surface molecules, cytokine secretion, gene induction as well as molecules of intracellular signal pathways concerned in immune activation [12-21]. These will be discussed in the presentation.

As to the implications of these biphasic changes in the dose-effect relationship, i.e., low dose stimulation and high dose suppression of immune activity, most important is its relation to cancer risks after exposure to LDR, which is of much concern to the public and academic spheres as well as regulatory bodies. Animal studies have demonstrated that LDR retards cancer growth, reduces metastasis, up-regulates the efficacy of conventional radio- and chemotherapy of cancer and alleviates the immune suppression caused by cancer burden [22-26]. Of special interest is the observation that LDR (0.025 to 0.1 Gy) 6~24 hours preceding each session of a high dose (1.5 Gy) given weekly for 4 consecutive weeks would reduce the incidence of thymic lymphoma in C57BL/6J mice to 1/3 or 1/2 of that occurring in the control which only received the high dose radiation. This suppressive effect of LDR on cancer incidence was found to be related to its stimulatory effect on immunity [27].

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