Immune Competence In Patients Research Articles

Evolutionary safety of lethal mutagenesis driven by antiviral treatment.

Nucleoside analogs are a major class of antiviral drugs. Some act by increasing the viral mutation rate causing lethal mutagenesis of the virus. Their mutagenic capacity, however, may lead to an evolutionary safety concern. We define evolutionary safety as a probabilistic assurance that the treatment will not generate an increased number of mutants. We develop a mathematical framework to estimate the total mutant load produced with and without mutagenic treatment. We predict rates of appearance of such virus mutants as a function of the timing of treatment and the immune competence of patients, employing realistic assumptions about the vulnerability of the viral genome and its potential to generate viable mutants. We focus on the case study of Molnupiravir, which is an FDA-approved treatment against Coronavirus Disease-2019 (COVID-19). We estimate that Molnupiravir is narrowly evolutionarily safe, subject to the current estimate of parameters. Evolutionary safety can be improved by restricting treatment with this drug to individuals with a low immunological clearance rate and, in future, by designing treatments that lead to a greater increase in mutation rate. We report a simple mathematical rule to determine the fold increase in mutation rate required to obtain evolutionary safety that is also applicable to other pathogen-treatment combinations.

Signaling Crosstalks Drive Generation and Regeneration of the Thymus.

Optimal recovery of immune competence after periods of hematopoietic insults or stress is crucial to re-establish patient response to vaccines, pathogens and tumor antigens. This is particularly relevant for patients receiving high doses of chemotherapy or radiotherapy, who experience prolonged periods of lymphopenia, which can be associated with an increased risk of infections, malignant relapse, and adverse clinical outcome. While the thymus represents the primary organ responsible for the generation of a diverse pool of T cells, its function is profoundly impaired by a range of acute insults (including those caused by cytoreductive chemo/radiation therapy, infections and graft-versus-host disease) and by the chronic physiological deterioration associated with aging. Impaired thymic function increases the risk of infections and tumor antigen escape due to a restriction in T-cell receptor diversity and suboptimal immune response. Therapeutic approaches that can promote the renewal of the thymus have the potential to restore immune competence in patients. Previous work has documented the importance of the crosstalk between thymocytes and thymic epithelial cells in establishing correct architecture and function of thymic epithelium. This crosstalk is relevant not only during thymus organogenesis, but also to promote the recovery of its function after injuries. In this review, we will analyze the signals involved in the crosstalk between TECs and hematopoietic cells. We will focus in particular on how signals from T-cells can regulate TEC function and discuss the relevance of these pathways in restoring thymic function and T-cell immunity in experimental models, as well as in the clinical setting.

Attenuation of apoptotic cell detection triggers thymic regeneration after damage.

SUMMARYThe thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.

From brain to brawn

After a subspecialized work day, when I opened the list of articles for the December issue of N2 I was reminded of how fascinating neurology is. There is an interesting group of studies that range from the CNS to the muscle and from acquired to innate immunity. For this corner, I selected only a few that represent the wide spectrum of topics. Alemtuzumab is a humanized monoclonal antibody that targets the membrane glycoprotein CD52, providing long-lasting suppression of disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). The underlying mechanisms resulting in these effects include complement-dependent cell lysis, antibody-dependent cellular cytotoxicity, and apoptosis leading to elimination of T cells. However, the effect of alemtuzumab on innate cells has been less investigated in patients with RRMS, and this is the main goal of the study of Gross et al.1 Innate immune cells comprise myeloid cells such as dendritic cells (DCs) and macrophages and lymphoid cells (ILCs), which include cytotoxic natural killer (NK) cells and 3 noncytotoxic tissue-resident subsets: ILC1, ILC2, and group 3 ILC (ILC3 and tissue-induced cells). The authors studied 12 patients with RRMS before and during alemtuzumab treatment and examined the effects on several of the above innate cell populations. They found that in comparison with CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets expressed lower amounts of CD52 on their surface. Interestingly, conventional DCs and plasmacytoid DCs that usually reconstitute rapidly in other immunosuppressive settings (e.g., allogeneic stem cell transplantation and immune conditioning) were found to be reduced 6 months after alemtuzumab treatment, although the interleukin (IL)–23 production in DCs was unchanged. In addition, within the ILC compartment, the subset of CD56bright NK cells expanded under alemtuzumab treatment but their cytolytic activity did not change. Interestingly, beneficial effects of daclizumab (a human monoclonal antibody against IL-2 receptor chain) are also associated with increasing numbers and function of the CD56bright NK cells in patients with RRMS, but different from alemtuzumab, daclizumab has effects on the cytolytic activity of NK cells. The authors acknowledge the limited number of patients and lack of functional assays in their study, but the findings are in line with the long-term efficacy of alemtuzumab, suggesting a remodeling of the innate immune system with preservation of immune competence in patients with RRMS.

"Ninjinto" (Ginseng Decoction), a Traditional Japanese Herbal Medicine, Improves Gastrointestinal Symptoms and Immune Competence in Patients with Chronic Intestinal Failure.

Background. Treating functional gastrointestinal disorders is extremely difficult. We herein report the effect of the oral administration of Ninjinto (NJT, ginseng decoction), a traditional Japanese Kampo medicine, on chronic intestinal failure. Patients and Methods. Seven patients with chronic intestinal failure treated with NJT were evaluated in this study. The primary diseases included chronic intestinal pseudoobstruction (CIPO: n = 4), short bowel syndrome (SBS: n = 2), and intestinal atresia (n = 1). All patients orally received NJT extract granules at a dose of 0.3 g/kg BW per day. The treatment outcomes were then assessed according to the patients' symptoms and consecutive abdominal X-ray findings. Results. The targeted symptoms were abdominal distension in four patients, diarrhea in three patients, and frequent hospitalization due to infections in two patients. An improvement in the symptoms was observed in six of the seven patients, whereas one patient with SBS did not show any improvement. An improvement in an abdominal roentgenogram was observed in the four patients with remarkably dilated bowel loops due to CIPO. Conclusions. NJT may be effective in controlling functional gastrointestinal disorders associated with chronic intestinal failure. The use of Kampo medicine in the field of pediatric surgery may help to improve the quality of life in children suffering from such conditions.

Regeneration of the aged thymus by a single transcription factor

Thymic involution is central to the decline in immune system function that occurs with age. By regenerating the thymus, it may therefore be possible to improve the ability of the aged immune system to respond to novel antigens. Recently, diminished expression of the thymic epithelial cell (TEC)-specific transcription factor Forkhead box N1 (FOXN1) has been implicated as a component of the mechanism regulating age-related involution. The effects of upregulating FOXN1 function in the aged thymus are, however, unknown. Here, we show that forced, TEC-specific upregulation of FOXN1 in the fully involuted thymus of aged mice results in robust thymus regeneration characterized by increased thymopoiesis and increased naive T cell output. We demonstrate that the regenerated organ closely resembles the juvenile thymus in terms of architecture and gene expression profile, and further show that this FOXN1-mediated regeneration stems from an enlarged TEC compartment, rebuilt from progenitor TECs. Collectively, our data establish that upregulation of a single transcription factor can substantially reverse age-related thymic involution, identifying FOXN1 as a specific target for improving thymus function and, thus, immune competence in patients. More widely, they demonstrate that organ regeneration in an aged mammal can be directed by manipulation of a single transcription factor, providing a provocative paradigm that may be of broad impact for regenerative biology.

Interleukin-22 drives endogenous thymic regeneration in mice (44.6)

Abstract Thymic regeneration is a crucial function that allows for renewal of immune competance after stress, infection or immunodepletion, however the mechanisms governing this rejuvenation remain poorly understood. Here we detail a framework of endogenous thymic regeneration centred on IL-22, a recently identified cytokine primarily implicated in maintenance of epithelial barrier function. Although IL-22 was redundant for steady-state thymopoiesis, thymic recovery was impaired in IL-22-deficient mice and intrathymic levels of IL-22 were significantly increased in WT mice following thymic damage. IL-22, which signalled through thymic epithelial cells and promoted their proliferation and survival, was upregulated by radio-resistant RORγ(t)+NKp46-CCR6+ lymphoid tissue-inducer cells after thymic injury under the control of dendritic cell-derived IL-23 and triggered by the depletion of CD4+CD8+ double positive (DP) thymocytes. Importantly, administration of IL-22 enhanced thymic recovery following irradiation damage. These studies reveal a network of endogenous thymus regeneration where 1) the depletion of DP thymocytes triggers 2) upregulation of IL-23 by DCs that induces 3) the production of IL-22 by thymic LTi. This cascade of events leads to regeneration of the epithelial microenvironment and, ultimately, to rejuvenation of thymopoiesis; presenting an innovative strategy for improving immune competence in patients whose thymus has been damaged from infection or cytoreductive therapy.

Innate Lymphoid Cell-Derived IL-22 Mediates Endogenous Thymic Repair Under the Control of IL-23

Abstract 143Despite being exquisitely sensitive to insult, the thymus is remarkably resilient in young healthy animals. Endogenous regeneration of the thymus is a crucial function that allows for renewal of immune competence following infection or immunodepletion caused by cytoreductive chemotherapy or radiation. However, the mechanisms governing this regeneration remain poorly understood. Thymopoiesis is a highly complex process involving cross-talk between developing thymocytes and their supporting non-hematopoietic stromal microenvironment, which includes highly specialized thymic epithelial cells (TECs) that are crucial for T cell development.IL-22 is a recently identified cytokine predominantly associated with maintenance of barrier function at mucosal surfaces. Here we demonstrate for the first time a critical role for IL-22 in endogenous thymic repair. Comparing IL-22 KO and WT mice we observed that while IL-22 deficiency was redundant for steady-state thymopoiesis, it led to a pronounced and prolonged loss of thymus cellularity following sublethal total body irradiation (SL-TBI), which included depletion of both thymocytes (p=0.0001) and TECs (p=0.003). Strikingly, absolute levels of IL-22 were markedly increased following thymic insult (p<0.0001) despite the significant depletion of thymus cellularity. This resulted in a profound increase in the production of IL-22 on a per cell basis (p<0.0001). These enhanced levels of IL-22 peaked at days 5 to 7 after SL-TBI, immediately following the nadir of thymic cellularity. This was demonstrated by a strong negative correlation between thymic cellularity and absolute levels of IL-22 (Fig 1a).In mucosal tissues the regulation of IL-22 production has been closely associated with IL-23 produced by dendritic cells (DCs) and ex vivo incubation of cells with IL-23 stimulates the production of IL-22. Following thymic insult there was a significant increase in the amount of IL-23 produced by DCs (Fig 1b) resulting in similar kinetics of intrathymic levels of IL-22 and IL-23. We identified a population of radio-resistant CD3−CD4+IL7Ra+RORg(t)+ thymic innate lymphoid cells (tILCs) that upregulate both their production of IL-22 (Fig 1c) and expression of the IL-23R (p=0.0006) upon exposure to TBI. This suggests that they are responsive to IL-23 produced by DCs in vivo following TBI and, in fact, in vitro stimulation of tILCs by IL-23 led to upregulation of Il-22 production by these cells (Fig 1d).We found expression of the IL-22Ra on cortical and medullary TECs (cTECs and mTECs, respectively), and uniform expression across both mature MHCIIhi mTEC (mTEChi) and immature MHCIIlo mTECs (mTEClo). However, in vitro stimulation of TECs with recombinant IL-22 led to enhanced TEC proliferation primarily in cTEC and mTEClo subsets (p=0.002 and 0.004 respectively). It is currently unclear if IL-22 acts as a maturation signal for mTECs, however, the uniform expression of IL-22Ra between immature mTEClo and mature Aire-expressing mTEChi, together with the preferential promotion of proliferation amongst mTEClo and cTEC seem to argue against IL-22 as a maturational signal but rather as promoter of proliferation, which ultimately leads to terminal differentiation of TECs. Of major clinical importance, administration of exogenous IL-22 led to enhanced thymic recovery (Fig. 1e) following TBI, primarily by promoting the proliferation of TECs. Consistent with this, the administration of IL-22 also led to significantly enhanced thymopoiesis following syngeneic BMT.Taken together these findings suggest that following thymic insult, and specifically the depletion of developing thymocytes, upregulation of IL-23 by DCs induces the production of IL-22 by tILCs and regeneration of the supporting microenvironment. This cascade of events ultimately leads to rejuvenation of the thymocyte pool (Fig. 1f). These studies not only reveal a novel pathway underlying endogenous thymic regeneration, but also identify a novel regenerative strategy for improving immune competence in patients whose thymus has been damaged from infection, age or cytoreductive conditioning required for successful hematopoietic stem cell transplantation. Finally, these findings may also provide an avenue of study to further understand the repair and regeneration of other epithelial tissues such as skin, lung and breast. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Effects of an immuno-enhanced diet containing antioxidants in esophageal cancer surgery following neoadjuvant therapy

Neoadjuvant therapy-induced immunological deterioration may be a key factor in postoperative morbidity in patients with esophageal cancer. This study aimed to determine the effects of perioperative feeding with an immuno-enhanced diet on immune competence in patients treated with neoadjuvant therapy followed by surgery. Because an immuno-enhanced diet that contained several antioxidants was used, perioperative oxidative stress and the effects of the immuno-enhanced diet on this stress were also investigated. Of 39 patients with esophageal cancer who underwent similar surgical procedures, 26 patients who received chemotherapy or chemoradiation therapy before surgery were randomly divided into two groups: group 1 (n= 14) was given an immuno-enhanced diet for 5 days before surgery, and group 2 (n= 12) received no enteral feeding products before surgery. Group 3 (n= 13) consisted of patients that did not receive neoadjuvant therapy and received no enteral feeding products before surgery. Several markers for coagulation and fibrinolysis were determined and immunological assessments were performed for each patient. To measure reactive oxygen metabolites and the total antioxidant capacity, diacron-reactive oxygen metabolites (d-ROMs) and OXY-adsorbent tests were performed using a free radical elective evaluator. Significant depression in lymphocyte numbers was observed in groups 1 and 2 before and early after surgery as compared to group 3. Numbers of B cells, CD4/CD8 ratio, and phytohemagglutinin-induced lymphocyte transformation tests were also significantly decreased in groups 1 and 2 on postoperative day 1. Fibrin and fibrinogen degradation products were significantly elevated in group 2 compared to group 1. d-ROMs and OXY-adsorbent test values were elevated before surgery and were decreased transiently early after surgery. Compared to groups 2 and 3, d-ROMs values were significantly lower in group 1 patients throughout the postoperative period, while OXY-adsorbent test values were significantly higher in group 2 patients. Oxidative index was significantly suppressed in group 1 compared to group 3. No significant intergroup differences were observed with regard to morbidity after surgery. Although the baseline levels of immunological function might have been different because of less-advanced cancer stages in group 3, neoadjuvant therapy significantly affected several immunological parameters. Preoperative administration of an immuno-enhanced diet did not significantly prevent neoadjuvant therapy-induced immunological deterioration prior to esophageal cancer surgery. Patients with esophageal cancer had elevated levels of oxidant and antioxidant activities before surgery, which were transiently decreased early after surgery. Although the underlying mechanisms for these perioperative changes are unclear, this study showed that an immuno-enhanced diet containing several antioxidants may reduce oxidative stress following esophageal cancer surgery. After these mechanisms are studied further, oxidative stress control may become another tool for perioperative management to reduce morbidity after esophageal cancer surgery.

T lymphocyte function in laryngectomized patients

Malignant tumors of the larynx account for 2.3% of all malignancies, while their frequency among tumors of the head and neck ranges between 12% and 20%. Research on the general immune competence in patients with malignant diseases has provided useful insight in the relationship between immune disorders on one side and the clinical course on the other. Unfortunately, only few complete studies have been published so far with this regard in patients with malignant tumors of the larynx, and therefore our study was essentially aimed at establishing of general immunocompetence, presence and levels of the possible immune disorders and their association with the malignant tumors. The study included forty two patients with primary squamocellular laryngeal cancer. All the patients underwent surgery, out of whom fifteen were treated postoperatively with radiotherapy. We tested the immune competence prior to the operation and in the postoperative period nine months later. In the venous blood we examined T lymphocyte function, monocyte levels and mononuclear phagocyte function. Preoperative evaluation of the presence and levels of general immune competence in patients with laryngeal cancer, showed a distinct decrease in the proliferative response to the PHA mitogen in vitro, with a tendency to normalize in patients who do not develop a relapse of the disease or distant metastasis during the follow-up period. During the whole study period, the number of monocytes and mononuclear phagocyte activity was above the normal level. The patients with operable laryngeal carcinoma had considerable immune disorders at various levels, primarily at the level of T lymphocytes. Of all the disorders, reduced mitotic activity of T lymphocytes in response to mitogens showed the highest dependance on the presence of malignant tissue in the organism.

Deficiency of cytomegalovirus (CMV)‐specific CD8+ T cells in patients presenting with late‐onset CMV disease several years after transplantation

Cytomegalovirus (CMV) is a major cause of morbidity and mortality among transplant recipients. The routine use of anti-CMV prophylaxis has modified the epidemiology of post-transplant CMV infection by delaying the onset of clinical disease. While the majority of delayed-onset CMV disease still occurs during the first year after transplant, reports of late-onset CMV disease presenting many years after transplantation are increasing. Here, we describe 2 CMV-seropositive transplant recipients who presented with late-onset CMV disease at 8 and 11 years after transplantation. To determine whether CMV disease occurring at a very late period after transplantation is related to immune competence, we assessed global and CMV-specific cellular immunity by evaluating the activation capability of CD8+ T cells to a mitogenic stimulus and by quantitative and functional analysis (as assessed by intracellular cytokine production and degranulation) of CMV-specific CD8+ T cells. In both patients, we demonstrated the absence or marked deficiency of CMV-specific T-cell immunity despite CMV seropositivity, and in one patient, a partial defect in the immune response to phorbol myristate acetate and ionomycin suggesting impaired global immune competence. Hence, our data suggest that late-onset CMV disease occurring many years after transplantation remains related to defects in the immune competence of patients. Measurement of CMV-specific cellular immune competence may therefore provide an additional tool to screen for patients at high risk of developing late-onset CMV disease. The clinical utility of this assay, however, will need to be evaluated in larger prospective studies.

Immune Response to Influenza Vaccine in Pediatric Patients With Inflammatory Bowel Disease

The aim of this study was to compare response to inactivated influenza vaccine in healthy children and pediatric patients with inflammatory bowel disease (IBD). A prospective, open-label, controlled clinical trial during influenza seasons of 2002-2004 was performed. Single-dose inactive trivalent influenza vaccine was administered. Immune response to vaccination was measured by pre-immunization and postimmunization hemagglutinin inhibition titers. A postimmunization hemagglutinin inhibition titer of 40 or higher was considered protective against influenza. IBD activity and adverse events were recorded. Eighty subjects were enrolled (29 healthy controls, 51 IBD patients). One patient did not complete the study. Patients were divided into 3 subgroups: infliximab and immunomodulatory (16), immunomodulatory (20), and anti-inflammatory therapy (14). Immunomodulatory therapy included corticosteroids, 6-mercaptopurine, or methotrexate. Overall, there was a statistically significant decrease in immune response in patients compared with healthy controls who received 1 influenza vaccine antigen (B/Hong Kong, P = .0125). Patients receiving infliximab and immunomodulatory therapy were less likely to respond to 2 influenza vaccine antigens (A/New Caledonia/20/99 and B/Hong Kong/330/2001, P = .018 and .0002, respectively). Fifteen subjects (19%) reported 19 mild adverse events: 11 (14%) reported soreness at the site, 4 (5%) reported having a cold, 3 (4%) reported flu-like symptoms, and 1 (1%) reported a headache. The clinical activity of IBD was not affected by vaccination. The serologic conversion rate to influenza vaccine in patients with IBD ranged from 33% to 85%. Patients on concomitant infliximab and immunomodulatory therapy are at risk of inadequate response to vaccination. The vaccine was safe and did not affect IBD activity.

Cytotoxic chemotherapy preceding apheresis of peripheral blood progenitor cells can affect the early reconstitution phase of naive T cells after autologous transplantation.

Transient T cell immunodeficiency is a common complication following hematopoietic stem cell transplantation. In breast cancer patients transplanted with autologous peripheral blood progenitor cells (PBPC) harvested after cytotoxic treatment with either cyclophosphamide or epirubicin plus paclitaxel, we evaluated T cells infused in grafts and in peripheral blood during the early reconstitution phase. We found that PBPC grafts harvested after treatment with epirubicin plus paclitaxel contained substantially larger numbers of T cells with less altered composition than after cyclophosphamide. Three months after high-dose cytotoxic chemotherapy, the numbers and the kinetics of circulating naive T cells, but not of memory and CD28- T cells, correlated positively with the number of naive T cells infused PBPC grafts. Finally, retrospective analysis of two cohorts of patients transplanted in different clinical settings with PBPC grafts harvested following cyclophosphamide or epirubicin plus paclitaxel showed apparently different susceptibilities to develop endogenous varicella zoster virus reactivation in the first year after high-dose cytotoxic chemotherapy. On the whole, these data indicate that number and composition of T cells in PBPC grafts vary according to the former cytotoxic therapy, and suggest that autologous transfer of T cells may accelerate the early T cell reconstitution phase and possibly ameliorate immune competence in patients rendered lymphopenic by high-dose chemotherapy.

Highly active antiretroviral therapy results in a decrease in CD8 + T cell activation and preferential reconstitution of the peripheral CD4 + T cell population with memory rather than naive cells

Objective: Highly active antiretroviral therapy (HAART) can produce marked increases in peripheral blood CD4 + T cells and decreases in HIV plasma RNA copy numbers. However, it is not clear whether these absolute changes will be accompanied by a recovery in the known naive CD4 + T cell depletion or a decrease in the marked CD8 + T cell activation. Design: Twenty-nine patients were enrolled in studies of either nucleoside therapy alone or nucleoside therapy combined with a protease inhibitor (zidovudine+lamivudine+indinavir). One hundred and ninety-one examinations were carried out at three baseline time points and during 40 weeks of follow-up to evaluate the effect of HAART on CD4 + memory/naive phenotype and CD8 + T cell activation. Methods: CD4 + and CD8 + T cell number, CD62L/CD45RA expression on CD4 + T cells and CD38 expression on CD8 + T cells were measured by three-color flow cytometry. Results: Most protease inhibitor treated patients had a significant rise in CD4 + numbers. The marked rise in the CD4 + T cells seen in individuals in this study was not accompanied over a 40-week period by a change in the abnormally low CD4 + naive compartment, and thus was almost completely of memory phenotype. The CD38 expression on CD8 + cells fell during treatment, and decreased to a greater degree than the comparable rise in CD4 + T cell counts. This decrease continued in many patients after the CD4 + T cell rise or viral load decline had plateaued. Conclusion: HAART results in changes in activation to a greater extent than absolute changes in CD4 + T cell numbers, but is not accompanied by an increase in naive CD4 + T cells. Measurements of CD4 + T cell numbers alone may not allow appropriate interpretation of immune activation or immune competence in patients receiving those drugs.

Antigen-specific Plaques Formation of Cultured Mononuclear Cells in Head and Neck Cancer

Antigen-specific antibody production in vitro from peripheral blood mononuclear cells was studied for the assessment of the immune competence of patients with head and neck cancer. Optimal culture conditions were studied using inactivated Staphylococcus aureus and a saturation with IL-1 during B cell activation and pooled human AB serum on day 2. After passage of the mononuclear cells through sephadex G-10 columns, a significant increase in the antigen-specific antibody production was observed. In healthy donors a significant reduction of the antigen-specific antibody production according to the abuse of alcohol and/or cigarette smoking was detectable. Interestingly, high alcohol consumption resulted in a more pronounced decrease of the antigen-specific antibody production in vitro than excessive cigarette smoking. Patients with squamous cell carcinoma of the head and neck who are considered to be most immunodeficient did not show any antigen-specific antibody production in vitro upon activation with sheep red blood cells in the presence of Interleukin-1 (IL-1). After filtration of mononuclear cells from peripheral bloodover sephadex G-10 beads, two thirds of the patients studied became stimulable. This increase in the antigen-specific antibody production in vitro was significant, though not as dramatic as in the age- and sex-matched control groups. Interestingly, the antigen-specific antibody production raised almost to the same level as that measured in healthy donors with high alcohol abuse and cigarette consumption.

Postoperative radiation therapy and adjuvant chemoimmunotherapy in breast cancer. Aspects of timing and immune competence.

The effects of radiation therapy and adjuvant chemoimmunotherapy on the immune competence of patients with breast cancer were investigated. The tests performed included intradermal tuberculin tests, T- and B-lymphocyte counts, and lymphocyte blast transformation tests; phytohemagglutinin (PHA), concanavalin A (ConA) and pokeweed mitogen (PWM) were used as mitogens. Enhancement in lymphocyte proliferative response to mitogenic stimulation by PHA and PWM was seen in patients after 3 courses of chemotherapy + levamisole, whereas irradiation given after chemotherapy caused long-lasting depression in response to PHA (p = 0.039) and PWM (not significant). T-lymphocyte counts were also lower after irradiation than after chemoimmunotherapy (p = 0.007). Clinically, the 16 patients treated with radiation therapy after chemotherapy exhibited a higher recurrence rate than the 24 patients treated first by irradiation. Enhanced reactivity to tuberculin tests occurred generally in patients receiving a planned treatment including irradiation, chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) and levamisole. Enhancement of reactivity was seen more often in patients who had not relapsed.

Lymphocyte subpopulations in patients with breast cancer after postoperative radiotherapy

The effects of radiotherapy on the immune competence of patients with mammary cancer was studied using enumeration of the various lymphocyte subpopulations as detected by monoclonal OKT antisera, lymphocyte proliferative responses to phytohemagglutinin, concanavalin A, purified protein derivative to tuberculin (PPD), and serum immunoglobulin levels. The tests were carried out in nine patients with newly diagnosed and operated mammary cancer before and after the radiation therapy, and 6 months later, and in ten patients whose mammary cancer had been diagnosed and treated at least 3 years earlier and who had remained tumor-free. The number of lymphocytes in the peripheral blood and the various T-cell subpopulations as well as the OKIa1 cells mostly representing B-cells decreased. The only population increasing were the OKM1-positive cells, mostly representing monocytes and null cells. As also described earlier, the responses to mitogens decreased because of the radiotherapy but recovered, except for the responses to PPD which remained low.

Adjuvant immunotherapy of carcinoma colli with levamisole: Prevention of immunological depression following surgical therapy and radiotherapy

Of 57 patients with carcinoma colli who underwent radical surgery followed by radiotherapy, 15 were treated with levamisole at a dose level of 150 mg a day for 3 consecutive days, every other week, starting 3 days before surgery. Another 17 patients received levamisole in the same manner except that the administration started simultaneously with post-operative radiotherapy. The immune competence of patients was determined in terms of immune globulin level, DNCB test, PHA skin test and lymphocyte blastogenic response to PHA, and was compared between the levamisole-treated group and the control group. Levamisole had little influence on immune globulin levels and skin reactions to PHA. The DNCB test after levamisole therapy showed no difference in the rate of positive response to DNCB between the levamisole group and the control group. Levamisole, when started before surgery, prevented the postoperative depression of lymphocyte responsiveness to to PHA and could more or less enhance the lymphocyte blast formation that had been depressed by radiotherapy.

Nutritional status and general immune competence in patients with head and neck cancer.

Anergy to 2,4-dinitrochlorobenzene (DNCB) has been reported as a highly significant adverse prognostic immunological factor in several studies of patients with squamous cell carcinomas involving the head and neck. Patients with these tumours often present with concurrent nutritional deficiencies. This paper reports the findings of a prospective study into both the nutritional status and general immune competence of 53 such patients.Analysis of the results has demonstrated a statistically highly significant positive correlation between nutritional status and both the delayed hypersensitivity response to DNCB, and the pretreatment total lymphocyte count levels. It is suggested that nutritional deficit may be a primary adverse prognostic factor in this disease group, with immunoincompetence a secondary phenomenon, and supporting evidence is presented. The consequent probable importance of nutritional status with regard to clinical trials, and the necessity for controlled studies to determine the possible beneficial effect of nutritional support on `cure' rates, are discussed.

Cell-mediated Immune Competence in Patients with Prostatic Carcinoma

AbstractThe immune competence of 65 patients with prostatic cancer was evaluated by 2 in vivo and 2 in vitro tests to study the contribution of host factors to the progress of the disease. Patients with benign prostatic hypertrophy served as controls. Our results indicate that the delayed skin hypersensitivity response to common microbial recall antigens (streptokinase/streptodornase, purified protein derivative, dermatophytin 0 and dermatophytin) is unaltered in advanced stages of malignancy. The ability to be sensitized by dinitrochlorobenzene declines significantly in patients with metastatic disease. Blastogenic response of peripheral blood lymphocytes to Phytohemagglutinin stimulation is not depressed in late stages of malignancy, although in the circulating T cells per cent and absolute values are somewhat lower in patients with metastases. Herein we show that immune competence (measured by the 4 tests) of patients with prostatic carcinoma does not decrease markedly even in the late stages of the disease. Primary sensitization to dinitrochlorobenzene is the only test showing a decline in responsiveness related to the tumor stage.