Immunology of tumor infiltrating lymphocytes.

Frequently peripheral blood lymphocytes (PBL) do not reflect the tumor host relationship and cell mediated immunity in the PBL does not often correlate with prognosis. The tumor infiltrating lymphocytes (TIL) interact most closely with the tumor cells and are likely to more accurately reflect tumor host interactions. These studies indicate that TIL from pulmonary tumors are similar to PBL so far as their cell surface markers are concerned. The percentage of T-cells, B-cells, helper cells, suppressor cells, and NK cells are similar in the two compartments. However, the TIL are markedly suppressed in their functional capacity as measured by their proliferative and cytotoxic activity. In addition, natural killer (NK) cell activity is markedly diminished in TIL as opposed to the PBL. In addition, the direct injection of BCG into these tumors reverses this phenomenon by significantly increasing T-cell and NK cell functional activity. Thus, the microenvironment of the tumor profoundly affects the immunologic relationship between the tumor and the host.     

Fas配体诱导淋巴细胞凋亡与肾癌免疫攻击作用

目的　探讨Fas配体 (FasL)诱导淋巴细胞凋亡与肾癌免疫攻击作用的关系。　方法　采用免疫组化技术检测 4 4例肾癌组织FasL表达及肿瘤周围浸润淋巴细胞 (TIL)凋亡情况 ,并应用肾癌细胞株 786 0、GRC 1与JurkatT淋巴细胞共培养检测T细胞凋亡率。SP法检测Ki6 7表达 ,评价肾癌预后。　结果　 (1) 4 4例肾癌组织FasL表达阳性率 4 6 .5 % ,高于正常肾组织的 2 3.2 % ,差别有显著性意义 (P <0 .0 1)。随肾癌分期增加 ,FasL表达阳性率增加。肾癌FasL表达率与Ki6 7表达率呈显著正相关 (r =0 .93,P <0 .0 1)。 (2 )肾癌组织TIL凋亡率为 33.9% ,高于正常肾组织的3.5 % ,差别有显著性意义 (P <0 .0 1)。肾癌FasL表达率与TIL凋亡率呈显著正相关 (r =0 .96 ,P <0 .0 1)。 (3) 786 0FasL表达率 18.6 % ,GRC 1表达率 2 .3% ,二者差别有显著性意义 (P <0 .0 1)。Ju rkat细胞与 786 0细胞共培养的凋亡率 14 .9% ,与GRC 1共培养的凋亡率 1.3% ,二者差别有显著性意义 (P <0 .0 1)。中和抗体NOK 2中和 786 0细胞FasL后 ,与之共培养的Jurkat细胞凋亡率显著减少 (P <0 .0 1)。　结论　肾癌组织FasL表达增高 ,以此诱导淋巴细胞凋亡 ,实现对宿主的免疫攻击。     

Study of cytotoxicity of recombinant interleukin-2 (rIL-2) expanded tumor infiltrating lymphocytes (TIL) in renal cell cancer

We studied subsets and cytotoxicity of recombinant interleukin-2 (rIL-2) expanded tumor infiltrating lymphocytes (TIL) from renal cell cancer (RCC) patients. TIL were successfully expanded in 13 of 14 RCC cases using anti-CD3 during initial 48 hours of culture. Percentages of CD8 positive cells among rIL-2 expanded TIL at 1 tp 4 week(s) of culture were 56.2 +/- 15.1% (range 26.2 to 79.8%, N = 13) and not necessarily predominant over CD4 positive cells. NK and LAK activities of TIL at 3 to 6 weeks of culture were 31.6 +/- 15.8% (range 1.4 to 57.4%, N = 9) and 16.6 +/- 11.6% (range 3.8 to 35.6%, N = 6), respectively. Autologous and allogeneic RCC cytotoxicity of TIL at 3 to 4 weeks of culture were 17.9 +/- 19.7% (range 0 to 47.6%, N = 4) and 18.9 +/- 14.8% (range 0 to 47.3%, N = 12), respectively. Since there was no statistical difference between them, autologous specific cytotoxicity was not demonstrated. From these results of present study, it is unlikely that most of effector cells of rIL-2 expanded TIL in autologous RCC lysis are major histocompatibility complex restricted cytotoxic T cells. And we concluded that it is doubtful that TIL is significantly superior over LAK cells in immunotherapy of human RCC.     

肿瘤浸润淋巴细胞在肾细胞癌原位表达的特点

目的:研究肾细胞癌组织中肿瘤浸润淋巴细胞(TIL)的分布特点及其与预后的关系.方法:对52例肾透明细胞癌组织T,辅助T及自然杀伤细胞(NK细胞)进行原位免疫组化研究,并与病人预后作相关性分析.结果:TIL细胞中主要为T细胞,占70%;TIL细胞表达的程度对肾细胞癌患者预后的影响较大(P<0.01);TIL细胞亚群之间的表达为正相关.结论:TIL在对抗肾细胞癌中起较重要的作用,它们的表达程度影响预后.     

经入肝血管行化学药物治疗对原发性肝癌浸润淋巴细胞及其功能的影响

目的探讨入肝血管区域性化学药物治疗（下称化疗）原发性肝癌的疗效机制。方法应用医学彩色图像分析,免疫组织化学染色,３ＨＴｄＲ掺入实验和乳酸脱氢酶释放测定等方法,对３６例接受全植入微泵肝动脉和门静脉输注化疗的原发性肝癌患者肿瘤浸润淋巴细胞的表型、组织密度,活化增殖功能和细胞毒活性进行检测。结果化疗后瘤体缩小获得二期切除者占６６６％（２４／３６）。其中Ｂ型超声和病理证实癌灶周围有明显包膜形成者占８３３％（２０／２４）,且癌灶内浸润淋巴细胞面积平均光密度和体积密度平均值较化疗前显著增高（Ｐ＜００１）,与化疗前和对照组比较,化疗后浸润淋巴细胞增殖活力虽有降低,但其浸润和抗肿瘤活性方面有显著改善;ＣＤ８＋、ＣＤ２５＋或ＨＬＡＤＲ＋亚群细胞呈高分布态势。结论入肝血管区域性化疗其机制不单纯涉及对肿瘤细胞的直接杀伤作用,而且可能与癌灶微环境内功能抑制的浸润淋巴细胞的功能调变密切相关     

Role of natural killer cells in bladder tumor

The role of natural killer (NK) cells in bladder tumors was assessed from the aspect of local and systemic immune responses. The NK cell activity was measured in a 4-hour 51Cr-release assay. The NK activity in patients with bladder tumor was lower, though not significantly, than that in normal individuals. In patients with bladder tumor, the NK activity was significantly lower in invasive tumors and lymph node metastases. Moreover, the NK activity was lower in those who died (n = 4) than it was in survivors (n = 21). In an in vitro experiment, OK432 significantly augmented the NK activity in peripheral blood lymphocytes (PBL), however, this augmentation was not always OK432 dose-dependent. The augmented NK activity induced by OK432 occurred even in patients with invasive tumors. On the other hand, the spontaneous NK activity in tissue-infiltrating lymphocytes (TIL) and lymph node lymphocytes (LNL) was significantly lower than that in PBL. In these three groups, the NK activity was significantly increased by OK432, this rate of increase was highest in TIL, followed by LNL and PBL. Further studies are required to elucidate the role of NK cells in bladder tumor, from the aspect of local and systemic immune responses.     

Dissociation Between T Helper Type 1 and Type 2 Differentiation and Cytokine Production in Tumor-Infiltrating Lymphocytes in Patients with Lung Cancer

We recently reported the balance of T helper type 1 (Th1) cells and type 2 (Th2) cells in patients with lung carcinomas. This study was conducted to investigate their activity and role in tumors, which remain unclear. We determined the population of lymphocytes with intracellular interferon (IFN)-γ or interleukin (IL)-4 by flow cytometry, and investigated cytokine production using enzyme-linked immunosorbent assay (ELISA) in 22 patients with non-small cell lung cancer. The IFN-γ-positive subset showed a significant increase in the number of tumor-infiltrating lymphocytes (TIL) compared with the peripheral blood lymphocytes (PBL) (PBL, 13.8% ± 1.5%; TIL, 34.3% ± 3.4%; P < 0.001), and the IL-4 positive subset showed reverse results (PBL, 3.7% ± 0.6%; TIL, 2.1% ± 0.3%; P = 0.037). However, TIL did not produce more IFN-γ than PBL. The results of intracellular IFN-γ analysis and the production of IFN-γ in PBL and TIL were significantly correlated (PBL: n = 22, r = 0.50, P = 0.025; TIL: n = 22, r = 0.44, P = 0.022). The dissociation between Th1 differentiation and IFN-γ production in TIL was one of the host factors influencing the immune anergy against tumors. Received: March 13, 2000 / Accepted: November 20, 2000     

Adriamycin-mediated potentiation of cytotoxicity against freshly isolated bladder cancer cells by autologous non-activated peripheral blood lymphocytes and tumor infiltrating lymphocytes

PURPOSE: Previous studies indicated that cancer patients lack functional anti-tumor cytotoxic lymphocytes. However, anti-tumor cytotoxic lymphocytes may coexist with immunoresistant tumor cells. We reasoned that anti-tumor cytotoxic activity of lymphocytes may be revealed if the tumor cells are sensitized to killing. It has been reported that adriamycin (ADR) exhibits various immunomodulating activities. In the present study, we investigate the effect of ADR on the susceptibility of freshly isolated bladder cancer cells to lysis by autologous non-activated peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL). MATERIALS AND METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. RESULTS: Treatment of ADR-resistant fresh bladder cancer cells with ADR at 0.1 microg./ml. or more for 3 hours or more enhanced their susceptibility to lysis by autologous PBL. This ADR-induced enhancement of susceptibility of fresh bladder cancer cells to lysis by PBL was also observed when lymphokine activated killer cells, purified natural killer cells and T lymphocytes were used as effector cells. Furthermore, while cytotoxicity of freshly derived TIL against autologous bladder cancer cells was minimal, significant cytotoxicity was observed with ADR-treated bladder cancer cells. The ADR analogs, epirubicin and pirarubicin, also enhanced the susceptibility of bladder cancer cells to lysis by autologous PBL. Treatment of bladder cancer cells with ADR had no effect on the expression of MHC class I on the cancer cells or the frequency of bladder cancer target cell conjugates to autologous PBL. Treatment of bladder cancer cells with ADR augmented their sensitivity to anti-Fas monoclonal antibody and tumor necrosis factor-a. Pretreatment of effector cells with ADR had no effect on their cytotoxic function. CONCLUSIONS: These findings demonstrate that PBL and TIL in patients with bladder cancer exhibit anti-tumor cytotoxic function, but their function is not manifested due to development or acquisition of tumor cell resistance to killing. However, the resistance of bladder cancer cells to killing by cytotoxic lymphocytes is overcome if cancer cells are sensitized by subtoxic concentrations of ADR. These findings suggest that treatment of bladder cancer patients with low doses of ADR may sensitize the cancer cells to killing by autologous circulating and tumor infiltrating lymphocytes and may be a novel immunotherapeutic modality for the treatment of drug-resistant and/or immune-resistant bladder cancer.     

Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma

Purpose

Renal cell carcinoma (RCC) is the most common cancer of kidney. Evidences have shown that RCC is sensitive to various immunotherapies. Tim-3 plays a role in suppressing Th1-mediated immune responses. However, no study has yet examined the effect of Tim-3 on tumor infiltrating lymphocytes (TILs) in RCC.

Methods

We investigated the expression and function of Tim-3 on TIL CD4+ T cells and TIL CD8+ T cells from 30 RCC patients.

Results

Levels of Tim-3 were significantly increased on both TIL CD4+ T cells and TIL CD8+ T cells and were associated with higher stages of the cancer. Also, GATA-3 and interferon gamma (IFN-γ) were down-regulated, whereas T-bet was up-regulated in TIL Tim-3+ T cells, indicating that Tim-3 expression defined a population of dysfunctional TIL Th1/Tc1 cells. Mechanism analyses showed that TIL Tim-3-expressing CD8+ T cells exhibited impaired Stat5 and p38 signaling pathway. Blocking the Tim-3 pathway restored cell proliferation and increased IFN-γ production in TIL CD4+ and CD8+ T cells of RCC.

Conclusions

These results suggest that Tim-3 may be used as a novel target for increasing immune responses in RCC tumor microenvironment.

     

Prognostic relevance of preoperative circulating CD8-positive lymphocytes in the urinary bladder recurrence of urothelial carcinoma

ObjectiveTumor-infiltrate lymphocytes (TIL) have been associated with favorable outcomes in various tumors including urothelial carcinoma (UC). There is little literature about peripheral blood lymphocytes (PBL). Our objective is to investigate the clinical significance and relevance of PBL on the outcomes of UC patients.Materials and methodsNinety UC treated patients at Chia-Yi Christian hospital were enrolled. Preoperative PBLs were collected and analyzed for the percentage of each subpopulation of lymphocyte using flow cytometry. The prognostic values were calculated by using Kaplan-Meier curve and Cox progression model for univariate and multivariate analyses, respectively. Furthermore, available tumor specimens from 27 patients were further analyzed for number of CD8⁺ tumor infiltrating lymphocytes (TIL) using immunohistochemistry. The correlation between percentage of CD8+ PBL and number of CD8+ TIL was analyzed using a linear regression model.ResultsThe log-rank test showed that tumor location (urinary bladder vs. upper urinary tract), enrolled status (primary or recurrent), and CD8⁺ PBL were significant prognostic indicators of recurrence (P values, 0.043, 0.039, and 0.018, respectively). Cox analyses showed that CD8⁺ PBL was the sole independent prognostic indicator for recurrence-free survival (P = 0.048). The results using a linear regression analysis showed there was a reverse correlation between CD8⁺ TIL and PBL (r² = 0.635, P < 0.0001).ConclusionsIn our investigation, preoperative CD8⁺ PBL was an independent predictor for bladder recurrence. The percentages of CD8⁺ PBL were reversely correlated with the number of TIL. Such findings may benefit in the decision for subsequent intravesical therapy after surgery.     

Prognostic significance of tumor infiltrating lymphocytes in melanoma

The prognostic significance of tumor infiltrating lymphocyte (TIL) response in cutaneous melanoma is controversial. This analysis of data from a prospective, randomized trial included patients with cutaneous melanoma > or = 1.0 mm Breslow thickness who underwent wide local excision and sentinel lymph node (SLN) biopsy. Univariate and multivariate analyses were performed to determine factors associated with TIL response, disease-free survival (DFS), and overall survival (OS). A total of 515 patients were included; TIL response was classified as "brisk" (n = 100; 19.4%) or "non-brisk" (n = 415; 80.6%). Patients in the nonbrisk TIL group were more likely to have tumor-positive SLN (17.6% vs 7%; P = 0.0087). On multivariate analysis, nonbrisk TIL response, increased tumor thickness, and ulceration were significant independent predictors of tumor-positive SLN. By Kaplan-Meier analysis, 5-year DFS rate was 91 per cent for those with a brisk TIL response compared with 86 per cent in the nonbrisk group (P = 0.41). The 5-year OS rates were 95 per cent versus 84 per cent in the brisk versus nonbrisk TIL groups, respectively (P = 0.0083). However, on multivariate analysis, TIL response was not a significant independent factor predicting DFS or OS. TIL response is a significant predictor of SLN metastasis but is not a major predictor of DFS or OS.     

Augmentation of cytotoxicity of tumor infiltrating lymphocytes by interleukin-2 in gastric cancer patients

Lymphocyte infiltration into tumor has been regarded as an expression of host reaction against tumor, but the natural cytotoxicity of tumor infiltrating lymphocytes (TLL) is often very low. In order to augment this low cytotoxicity, TIL of gastric cancer patients were cultured with interleukin-2 (IL-2) in vitro. On the other hand, immunopotentiators (OK432, PSK) were injected into gastric cancer intralesionally under endoscopy. By the in-vitro culture with IL-2, the cytotoxicity of TIL was augmented against both targets of K562 and MNN28 (gastric carcinoma cell line). In particular, the augmentation of cytotoxicity against MKN28 was more obvious in TLL than PBL (peripheral blood lymphocytes). In the ascitic lymphocytes, the in-vitro culture with IL-2 induced autologous tumor cell killing. Intralesional injection of OK432 or PSK augmented the natural cytotoxicity of TIL, and the ratio of OKT8 and Leu7 cells increased in the TIL of OK432-injected group.     

The prognostic value of liver tumor T cell infiltrates

Tumor infiltrating lymphocytes (TIL) have been demonstrated to predict oncologic outcomes following resection of primary intrahepatic neoplasms and metastatic liver tumors. Despite strong immunosuppressive factors within the intrahepatic space, TIL are frequently demonstrated in liver tumors. The presence of TIL within liver tumors provides evidence of a host immune response that may be protective, but often is rendered ineffective by tumor induced immune dysfunction. In this review, we discuss techniques involved in studying TIL and subsets of TIL commonly identified. We emphasize the unique nature of the intrahepatic milieu that promotes immunosuppression, and how liver TIL and TIL ratios can be used as indicators of prognosis. Several types of primary and metastatic liver tumors are considered to highlight the similarities and important differences in TIL responses, which likely reflect how intrahepatic immunity is influenced by tumor biology. The studies we discuss indicate that tumor infiltration by suppressor cells and expression of immunoinhibitory molecules by TIL limits the anti-tumor immune function of effector T cells. Most patients fail to mount an adequate immune response to liver tumors, which provides compelling rationale for clinical study of immunotherapy for intrahepatic neoplasms.     

直肠癌旁移行粘膜中γδ T细胞含量及受体基因重排的研究

目的 探讨直肠癌旁移行粘膜中γδＴ细胞含量和受体基因重排表达情况与直肠癌局部复发之间的关系,方法 运用双色免疫荧光标记流式细胞仪分析法和多聚酶链反应技术,检测１３例中低位直肠癌患者的癌旁移行粘膜上皮淋巴细胞（ＴＭＬ）,肿瘤浸润淋巴细胞（ＴＩＬ）,正常直肠粘膜上皮淋巴细胞（ＩＥＬ）中γδＴ细胞含量,γδＴ细胞受体δ链可变区（γδ－ＴＣＲＶδ）基因重排表达。结果 ＴＭＬ中γδＴ细胞的含量显著地高于ＴＩ     

Study on adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) for renal cell carcinoma--amplification of IL-2-elicited TIL proliferation by OKT3-monoclonal antibody

Human autologous peripheral blood lymphocytes (PBL) and lymphocytes infiltrating renal cell carcinoma (TIL) were cultured with medium containing 1000 IU/ml of human interleukin 2 (IL-2). A high cytotoxic activity against fresh autologous as well as cultured allogenic tumor cells was developed. By culturing these lymphocytes with OKT3 monoclonal antibody during the initial 2 days of long-term culture, in terms of T cell activation signal, IL-2-driven lymphocyte proliferation was remarkably accelerated with maintenance of appreciable level of cytotoxic activity. The same culture method also induced an increase in OKT3 and IL-2 receptor positive lymphocyte population in LAK cells and TIL. This method may enable us to gain more autologous TIL in vitro for adoptive immunotherapy of renal cell carcinoma than the usual culture method with IL-2 alone. Five patients with metastatic renal cell carcinoma were treated with adoptive immunotherapy with TIL, LAK and IL-2. One patient with pulmonary metastasis has had a minor response which has lasted for 3 months so far. We have not experienced any serious side effects during the treatment.     

Changes on distribution of CD4+/CD45RA- and CD8+/CD11- cells in tumor-infiltrating lymphocytes of renal cell carcinoma associated with tumor progression.

To study the distribution of subsets of T cells in renal cell carcinoma, peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) were analyzed in 43 untreated patients using two-color flow cytometry. An increase in the relative number of CD4+/CD45RA-, CD8+/CD11- and HLA-DR+/CD3+ cells was shown in TIL when compared with PBL. When the influence of various tumor factors on subsets of TIL was examined, a decrease in CD4, CD4+/CD45RA- and CD16+/CD57- cells and an increase in CD8+ and CD8+/CD11- cells was observed along with the aggravation of tumor stage and grade. In TIL of stage III/IV and grade III/IV disease, most patients showed an increase in CD8+/CD11- associated with a decrease in CD4+/CD45RA- cells, or the reverse, resulting in changes of the CD4+/CD45RA- to CD8+/CD11- ratio. The prognosis for these patients was poor, suggesting that changes in the ratio were a sign of the impairment of local immune status associated with disease progression.     

Immunological assessment of tumour infiltrating lymphocyte subsets in renal cell carcinoma patients. An analysis of immunological reaction to immuno-competent lymphocytes by interferon-gamma

Twenty-two patients with renal cell carcinoma subjected to radical nephrectomy were divided into 2 groups. The first group consisted of patients who received nephrectomy alone, and the second of 10 patients who received pre-operative IFN-gamma. Using monoclonal anti-bodies of each subset of lymphocytes, immunological distributions of tumour infiltrating lymphocytes (TIL) were evaluated by means of immunohistochemical staining and the peripheral blood lymphocytes (PBL) were evaluated by flow-cytometry. Furthermore, immunological effects of IFN-gamma on these immuno-competent cells were investigated. The effect of IFN-gamma on TIL was an increase in CD3 (pan-T cells), in particular an increase in CD8 (suppressor/cytotoxic-T cells). On the other hand, a significant increase in CD16 alone was found on PBL. As to the TIL according to stages, all subset ratios tended to be higher in high stage patients without administration of IFN-gamma. With pre-administration of IFN-gamma, a marked increase in CD3 was found among low stage patients. In examining these cells according to grades, no specific trend was observed between low and high grade patients without having IFN-gamma administration. With pre-administration of IFN-gamma, an increase in CD3 and CD8 was observed in low grade patients. As to PBL, a significant increase in CD16 alone was observed with pre-administration of IFN-gamma, and no correlation was found between stage and grade. We draw the conclusions that the subsets of TIL were quite different from those of PBL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tumor-infiltrating lymphocytes and histocompatibility antigens in primary intracranial germinomas

Subpopulations of tumor-infiltrating lymphocytes (TIL's) and the major histocompatibility complex (MHC) antigens of neoplastic cells were examined in three intracranial germinomas by an immunohistochemical method using monoclonal antibodies. About 70% to 80% of TIL's were T lymphocytes which were either infiltrating diffusely or in clusters, whereas 20% to 30% of TIL's were B lymphocytes which tend to cluster in tumor tissues. Examination of T lymphocyte phenotypes revealed both the cytotoxic/suppressor and helper/inducer T lymphocytes, as in other tumors. However, the existence of a considerable number of B lymphocytes in the TIL population was uncommon and seemed to be a characteristic feature of the intracranial germinoma, which might suggest a difference of host immune response to this neoplasm as compared to other tumors. On examination of the MHC antigens, no MHC class I or II antigens in the neoplastic cells were stained, while positive staining for both antigens was seen in the TIL and stroma tissues. From these findings, it was suggested that the degree of TIL infiltration might not be correlated with the expression of MHC antigens in neoplastic cells in cases of primary intracranial germinoma.     

Activation by the protein-bound polysaccharide PSK (krestin) of cytotoxic lymphocytes that act on fresh autologous tumor cells and T24 human urinary bladder transitional carcinoma cell line in patients with urinary bladder cancer

PSK, a protein-bound polysaccharide Kureha, was tested for its ability to modulate the cytotoxicity of lymphocytes that act on autologous tumor cells and T24 human urinary bladder tumor cells in urinary bladder cancer patients in a 6-h 51Cr release assay. In vitro treatment of peripheral blood lymphocytes (PBL) with PSK for 18 hours resulted in an augmentation or induction of cytotoxicity against relatively resistant T24 cells in previously reactive and nonreactive cases, respectively. The PSK-treated PBL were able to kill more effectively tumor cells that were freshly isolated from the same cancer patients than non-treated PBL. The effects of PSK were noted with PBL as well as tumor infiltrating lymphocytes (TIL) and with PSK at concentrations of 10 to 100 micrograms./ml., while PSK at higher doses reduced their lytic activities. The addition of PSK to the assay at the same concentrations also enhanced the cytotoxicities. Autologous tumor killing (ATK) activities of both large granular lymphocytes (LGL) and T lymphocytes were enhanced by PSK. Treatment of PBL with PSK did not effect on the proportion of PBL binding to the tumor cells, while it augmented the cytotoxic activity. Cell-free supernatant of PSK-stimulated lymphocyte culture did not contain any detectable amounts of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). In addition, anti-IFN-alpha monoclonal antibody (MAb), anti-IFN-gamma MAb and anti-IL-2 MAb did not inhibit PSK-induced augmentation of cytotoxicity against T24. Oral administration of PSK (three gm./day) to patients with urinary bladder cancer daily for seven days before operation resulted in an augmentation of the cytotoxicity against T24 cells in five out of 10 patients and no change of the cytotoxicity in the other five patients. ATK activity was also enhanced by oral administration of PSK in three out of five patients. These results indicate that the antitumor activity of PSK may be in part mediated through activation of tumor killing system independent of IFN-alpha, IFN-gamma and IL-2.     

Impaired cellular immune responses in chronic renal failure: evidence for a T cell defect

Cellular immune responses in vitro were studied in 24 patients on chronic hemodialysis and 16 healthy volunteers with normal kidney function. Patients on maintenance hemodialysis had lymphopenia with diminished numbers of both T4+ and T8+ T-lymphocytes. The T4/T8 ratios were within the normal range. Peripheral blood lymphocytes (PBL) showed a diminished proliferative response upon stimulation with concanavalin A, phytohemagglutinin and pokeweed mitogen. When cell surface antigens were used for stimulation (mixed lymphocyte culture) uremic lymphocytes also showed a lower proliferation rate. Although without statistical conformation, there was a tendency by uremic PBL to produce less IL-2 as compared to healthy controls. Moreover, in a PWM driven system, peripheral blood lymphocytes from uremics produced significantly less IgG than PBL from normals. These results support the notion that a profound defect in lymphocyte function accounts at least, in part, for the observed immunodeficiency of uremic patients.