SEOM clinical guidelines in hereditary breast and ovarian cancer (2019).

Mutations in BRCA1 and BRCA2 high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers.

SEOM-SERAM-SEMNIM guidelines on the use of functional and molecular imaging techniques in advanced non-small-cell lung cancer. / Guía SEOM-SERAM-SEMNIM sobre el empleo de las técnicas de imagen funcional y molecular en el cáncer de pulmón no microcítico avanzado.

Imaging in oncology is an essential tool for patient management but its potential is being profoundly underutilized. Each of the techniques used in the diagnostic process also conveys functional information that can be relevant in treatment decision making. New imaging algorithms and techniques enhance our knowledge about the phenotype of the tumor and its potential response to different therapies. Functional imaging can be defined as the one that provides information beyond the purely morphological data, and include all the techniques that make it possible to measure specific physiological functions of the tumor, whereas molecular imaging would include techniques that allow us to measure metabolic changes. Functional and molecular techniques included in this document are based on multi-detector computed tomography (CT), 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), magnetic resonance imaging (MRI), and hybrid equipments, integrating PET with CT (PET/CT) or MRI (PET-MRI). Lung cancer is one of the most frequent and deadly tumors although survival is increasing thanks to advances in diagnostic methods and new treatments. This increased survival poises challenges in terms of proper follow-up and definitions of response and progression, as exemplified by immune therapy-related pseudoprogression. In this consensus document, the use of functional and molecular imaging techniques will be addressed to exploit their current potential and explore future applications in the diagnosis, evaluation of response and detection of recurrence of advanced NSCLC.

Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain.

OBJECTIVE: Patients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model. METHODS: One hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1 week, 3 months, and 12 months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty. RESULTS: A pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value = .87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value <.001). Most of the patients reported the wish to know all genetic results. CONCLUSIONS: Our results suggest that patients can psychologically cope with cancer panel testing, but distress and uncertainty observed in carriers of moderate penetrance cancer variants in this cohort warrant further research.

SEOM-SERAM-SEMNIM guidelines on the use of functional and molecular imaging techniques in advanced non-small-cell lung cancer.

Imaging in oncology is an essential tool for patient management but its potential is being profoundly underutilized. Each of the techniques used in the diagnostic process also conveys functional information that can be relevant in treatment decision-making. New imaging algorithms and techniques enhance our knowledge about the phenotype of the tumor and its potential response to different therapies. Functional imaging can be defined as the one that provides information beyond the purely morphological data, and include all the techniques that make it possible to measure specific physiological functions of the tumor, whereas molecular imaging would include techniques that allow us to measure metabolic changes. Functional and molecular techniques included in this document are based on multi-detector computed tomography (CT), 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), magnetic resonance imaging (MRI), and hybrid equipments, integrating PET with CT (PET/CT) or MRI (PET-MRI). Lung cancer is one of the most frequent and deadly tumors although survival is increasing thanks to advances in diagnostic methods and new treatments. This increased survival poises challenges in terms of proper follow-up and definitions of response and progression, as exemplified by immune therapy-related pseudoprogression. In this consensus document, the use of functional and molecular imaging techniques will be addressed to exploit their current potential and explore future applications in the diagnosis, evaluation of response and detection of recurrence of advanced NSCLC.

Preventive treatments for breast cancer: recent developments.

Breast cancer is a burden for western societies, and an increasing one in emerging economies, because of its high incidence and enormous psychological, social, sanitary and economic costs. However, breast cancer is a preventable disease in a significant proportion. Recent developments in the armamentarium of effective drugs for breast cancer prevention (namely exemestane and anastrozole), the new recommendation from the National Institute for Health and Care Excellence to use preventative drugs in women at high risk as well as updated Guidelines from the US Preventive Services Task Force and the American Society of Clinical Oncology should give renewed momentum to the pharmacological prevention of breast cancer. In this article we review recent major developments in the field and examine their ongoing repercussion for breast cancer prevention. As a practical example, the potential impact of preventive measures in Spain is evaluated and a course of practical actions is delineated.

Low dose gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane-anthracycline-containing regimens.

PURPOSE: Cisplatin-gemcitabine is a synergistic chemotherapy (CT) combination highly proven in a broad spectrum of epithelial neoplasms and shows a non-cross-resistance profile with the most active drugs in metastatic breast cancer (MBC). We have conducted an exploratory study to determine if treatment with low doses of a combination of fixed-rate gemcitabine infusion and cisplatin was clinically meaningful in women relapsing after a minimum of 2 prior lines of CT for advanced disease (range 2-6), which had to have necessarily included both anthracyclines and taxanes. Another goal was to find the optimal individual schedule by adjusting frequency and dosage according to patient tolerability. PATIENTS AND METHODS: From May 2002 to November 2003, 22 patients with relapsed advanced BC and a minimum of two prior CT lines were offered treatment with gemcitabine (G) (initial dose 750 mg/m(2), or 600 mg/m(2) if the patient had received more than two previous CT lines) plus cisplatin (P) (initial dose 30 mg/m(2), or 20 mg/m(2) in case of > or =3 prior CT lines) on days 1 and 8 of a 21-day cycle. Treatment was postponed to day 15 if it could not be given on day 8, without dose reduction. If treatment could not be given on day 15, a 20% dose reduction was allowed and treatment given the next week. Further dose reductions were allowed as needed up to a maximum of three. Treatment continued until disease progression or intolerable toxicity. Median age was 54.5 years (35-75). Median Karnofsky was 90 (range 80-90). Median number of prior CT lines was 3 (2-6). 90.9% of patients had received adjuvant CT. All had prior anthracyclines and taxanes. Other agents used included 5-FU/eniluracil, MTA, RPR 109881A, trastuzumab, cisplatin, VP16, vinorelbine, capecitabine and irinotecan. 72.7% had received radiotherapy and 68.1% hormonal therapy (median 2 lines, range 1-4). RESULTS: Partial responses (PR) were seen in 9.1% of patients and stable disease (SD) in 36.4%. Clinical Benefit Rate (PR+SD) was derived in 45.5% of patients. Median time to progression was 4 months (95% CI, 3-5) in general and 6 months (95% CI, 4-8) in patients with clinical benefit. Median survival for the entire group was 8 months (95% CI, 5-11) and 19 months when clinical benefit was obtained (95% CI, 11-25). Patients received a median of 8.5 CT administrations (range, 2-45). Forty-three percent of doses were delayed. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Cisplatin and gemcitabine doses were reduced in 75% and 62% of all cycles, respectively. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Toxicities grade >3 were neutropenia 35% and thrombocytopenia 15%. All other toxicities were grade 2 or less, including sensorial neuropathy (30%), asthenia (34%), nausea/vomiting (20%) and oral mucositis (15%). There were no treatment-related deaths. Reasons for discontinuation were progression (18 patients), death (3 patients) and patient decision (1 patient). CONCLUSION: Weekly cisplatin-gemcitabine with flexible downwards individual tailoring is a safe and effective salvage treatment in heavily pretreated MBC patients with good PS.

Low dose gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane-anthracycline-containing regimens

PURPOSE: Cisplatin-gemcitabine is a synergistic chemotherapy (CT) combination highly proven in a broad spectrum of epithelial neoplasms and shows a non-cross-resistance profile with the most active drugs in metastatic breast cancer (MBC). We have conducted an exploratory study to determine if treatment with low doses of a combination of fixed-rate gemcitabine infusion and cisplatin was clinically meaningful in women relapsing after a minimum of 2 prior lines of CT for advanced disease (range 2-6), which had to have necessarily included both anthracyclines and taxanes. Another goal was to find the optimal individual schedule by adjusting frequency and dosage according to patient tolerability. PATIENTS AND METHODS: From May 2002 to November 2003, 22 patients with relapsed advanced BC and a minimum of two prior CT lines were offered treatment with gemcitabine (G) (initial dose 750 mg/m(2), or 600 mg/m(2) if the patient had received more than two previous CT lines) plus cisplatin (P) (initial dose 30 mg/m(2), or 20 mg/m(2) in case of > or =3 prior CT lines) on days 1 and 8 of a 21-day cycle. Treatment was postponed to day 15 if it could not be given on day 8, without dose reduction. If treatment could not be given on day 15, a 20% dose reduction was allowed and treatment given the next week. Further dose reductions were allowed as needed up to a maximum of three. Treatment continued until disease progression or intolerable toxicity. Median age was 54.5 years (35-75). Median Karnofsky was 90 (range 80-90). Median number of prior CT lines was 3 (2-6). 90.9% of patients had received adjuvant CT. All had prior anthracyclines and taxanes. Other agents used included 5-FU/eniluracil, MTA, RPR 109881A, trastuzumab, cisplatin, VP16, vinorelbine, capecitabine and irinotecan. 72.7% had received radiotherapy and 68.1% hormonal therapy (median 2 lines, range 1-4). RESULTS: Partial responses (PR) were seen in 9.1% of patients and stable disease (SD) in 36.4%. Clinical Benefit Rate (PR+SD) was derived in 45.5% of patients. Median time to progression was 4 months (95% CI, 3-5) in general and 6 months (95% CI, 4-8) in patients with clinical benefit. Median survival for the entire group was 8 months (95% CI, 5-11) and 19 months when clinical benefit was obtained (95% CI, 11-25). Patients received a median of 8.5 CT administrations (range, 2-45). Forty-three percent of doses were delayed. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Cisplatin and gemcitabine doses were reduced in 75% and 62% of all cycles, respectively. Sixteen out of 22 patients needed a delay and/or reduction of initial dose. Toxicities grade >3 were neutropenia 35% and thrombocytopenia 15%. All other toxicities were grade 2 or less, including sensorial neuropathy (30%), asthenia (34%), nausea/vomiting (20%) and oral mucositis (15%). There were no treatment-related deaths. Reasons for discontinuation were progression (18 patients), death (3 patients) and patient decision (1 patient). CONCLUSION: Weekly cisplatin-gemcitabine with flexible downwards individual tailoring is a safe and effective salvage treatment in heavily pretreated MBC patients with good PS (AU)

Quimioprevención del cáncer de mama / Chemoprevention of breast cancer

La prevención farmacológica (quimioprevención) del cáncer de mama es el nuevo reto de la modernaoncología médica en el ámbito de este tumor, el más frecuente en la población femenina mundial. Laextensión de los programas de cribado (detección precoz) y los avances en la farmacología terapéutica hanconseguido que en la última década se registre un descenso constante en la mortalidad por esta enfermedad.Sin embargo, las tasas de incidencia continúan aumentando o cuando menos estabilizadas, lo cual hace, juntoa la creciente proporción de mujeres en seguimiento después de completar el tratamiento adyuvante, que lacarga médica y social del cáncer de mama continúe creciendo. Por ello, la consecución de un medicamentoeficaz, seguro y tolerable que disminuya la incidencia del tumor es un objetivo altamente deseable. En laactualidad, una vez demostrado el potencial de la inhibición estrogénica con tamoxifeno para prevenir laaparición del cáncer de mama, se investiga activamente el papel de otros SERMS y algunos inhibidores de laaromatasa para conseguir un cociente riesgo-beneficio favorable en segmentos muy amplios de la población

The pharmacological prevention (chemoprevention) of breast cancer is the new challenge of modernmedical oncology to deal with a kind of tumor that is the most frequent among the female population all overthe world. The extension of the screening programs for early-stage detection and the advances in therapeuticpharmacology have achieved a continued reduction in breast cancer mortality in the last decade. However, theincidence rate continues increasing or is at least stable, what considered together with the increasingproportion of women in follow-up after completing the adjuvant treatment, leads to a continued increase of themedical and social burden of breast cancer. For this reason, the securing of an efficacious, safe and tolerateddrug diminishing the tumor incidence is a very desirable objective. Presently, once demonstrated thattamoxifen-mediated estrogenic inhibition can prevent the appearance of breast cancer, the research of the roleof other SERMs (Selective Estrogen Receptor Modulators) and aromatase inhibitors is very active, looking forproducts having a favorable risk-benefit ratio that will make then useful for wide groups of population

Do changes in dietary salt influence blood pressure of hypertensive patients pharmacologically controlled with verapamil? The Salt-Switching-Study (SSS).

To study how changes in dietary salt influence the blood pressure (BP) of pharmacologically controlled hypertensive patients, we have selected from a large multicenter trial two subgroups of 14 and 16 patients who attained BP control (office DBP < 90 mm Hg) after a 4-week treatment with verapamil SR 240 mg once daily, either under an unrestricted salt diet (high-salt; 14 patients) or under a moderately restricted salt diet (low-salt; 16 patients). All of them were switched to the opposite dietary salt regimen and continued on verapamil for 4 more weeks (Salt-Switching-Period). Office BP and ambulatory blood pressure monitoring (ABPM) were registered before and after the Salt-Switching-Period. Salt intake was checked by urinary sodium excretion (UNa). Patients switching from high- to low-salt reduced UNa from 180.9 +/- 22.9 to 89 +/- 28 mM Na/24h (P < 0.001) and patients switching from low- to high-salt increased UNa from 85 +/- 38.4 to 175.8 +/- 57.5 mM Na/24h (P < 0.001). No significant changes in BP were found by ABPM either in the group switching from high- to low-salt or in the group switching from low- to high-salt. In the latter group, a significant increase was observed in office DPB but not in SBP. Short-term changes in salt intake seem to have little influence on the BP of patients pharmacologically controlled with verapamil.

Programmed cell death by bcl-2-dependent and independent mechanisms in B lymphoma cells.

Programmed cell death (PCD) or apoptosis is a common form of cellular demise during embryogenesis, tumorigenesis and clonal selection in the immune system. The bcl-2 proto-oncogene has been recently implicated as a potential physiological regulator of the PCD pathway. Gene transfer studies have shown that overexpression of bcl-2 blocks apoptosis mediated by several stimuli in cultured cell lines and promotes the survival of B and T lymphocytes in transgenic mice. However, it remains unclear whether under normal conditions bcl-2 is responsible for controlling cell death. We have investigated the role of bcl-2 in the antimembrane IgM (mIgM)-induced apoptotic death of WEHI-231 B cell lymphoma, a model that mimics clonal deletion of immature B cells by antigen. Signalling of mIgM receptors triggered downregulation of both bcl-2 RNA and protein, and induced apoptosis in WEHI-231 B cells. This effect appeared to be specific since (i) the levels of beta 2-microglobulin and beta-actin RNA remain unchanged and (ii) signalling of the apoptosis-resistant B cell lymphoma line BAL-17 with anti-mu was not associated with downregulation of bcl-2 RNA. However, stable expression of bcl-2 by transfection did not rescue WEHI-231 B cells from apoptosis, yet WEHI-231 cells overexpressing bcl-2 were more resistant to programmed cell death induced by heat-shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin E2 induces apoptosis in immature normal and malignant B lymphocytes.

The purpose of this research was to determine whether prostaglandin E2 (PGE2), a major product of macrophages which can kill certain murine B cell lymphomas, induces death by a necrotic mechanism or by an alternate pathway called apoptosis. CH31 is a phenotypically "immature" B cell lymphoma which resembles immature neonatal B cells in its susceptibility to killing by reagents which cross-link surface immunoglobulin (sIg). In the present study we first show that PGE2, but not the closely related prostanoid, PGF2 alpha, kills CH31 lymphoma cells. In contrast, CH12, a phenotypically "mature" lymphoma which is not negatively affected by sIg cross-linking, is not induced to die after exposure to PGE2. Agarose gel electrophoresis demonstrated that the DNA of PGE2-treated CH31, but not CH12 cells, is cleaved into characteristic 200 base pair oligonucleosomal fragments indicative of an apoptotic mechanism of death. However, a necrotic form of death, indicated by random DNA cleavage which produces a smear following electrophoresis, could be induced by treatment of CH12 or CH31 with anti-class II MHC antibodies and complement. The apoptotic mechanism of CH31 cell killing by PGE2 was confirmed using scanning electron microscopy which demonstrated the unique membrane blebbing and bubbling pathognomonic of this form of death. Finally, using a recently devised flow cytometric method to study apoptosis in heterogeneous cell populations, we compared the ability of anti-IgM, PGE2, or PGF2 alpha to induce apoptosis in B lymphocytes from neonatal or adult mice. Anti-IgM, and to a lesser extent PGE2, but not PGF2 alpha, induces apoptosis in a fraction of neonatal B cells. None of these treatments induced cell death in B lymphocytes from mature mice. Overall, these observations suggest that PGE-secreting cells such as macrophages, which inhabit the B cell microenvironments of lymphoid organs, may eliminate a subset of immature B lymphocytes and may be important in controlling the spread of PGE-sensitive malignant B lymphoma cells.

Prevention of B cell clonal deletion and anergy by activated T cells and their lymphokines.

B cell tolerance is described as the absence of a measurable antibody forming response to an antigenic challenge. The establishment of antigen-specific tolerance requires, by definition, engagement of the B cell antigen-specific receptor. However, only in some circumstances does this engagement lead to tolerance, while in others it produces B cell activation and secretion of immunoglobulins. Several mechanisms occur naturally in vivo abrogating the expression of deleterious autoantibodies and contributing to the state of self-tolerance. In this review, we will examine different ways in which B cell tolerance can be broken, focusing on evidence showing that activated-T cells and/or their lymphokines can prevent B cell clonal deletion and thus have a potential role in the pathogenesis of autoimmune diseases. This approach is based on the well-known association of several lymphokines, such as IL-1, IL-2, IL-4, IL-5, and type I interferons, with autoimmune phenomena in vivo.

Inability of IL-2 and IL-10 to counteract B cell clonal deletion.

The B cell antigen receptor (BCR) delivers inhibitory signals in nascent B cells leading to the establishment of tolerance via clonal deletion or clonal anergy depending upon the type of antigen to which the B cells are exposed. In previous work, it has been demonstrated that activated Th2 cells, as well as some recombinant lymphokines, prevent the inhibition of growth and subsequent cell death induced through the BCR in model B cell lymphomas. Herein, we extend this work to another Th2 lymphokine, IL-10, that in contrast to IL-4 does not interfere with the deletion promoted by IgM crosslinking. The effect of individual lymphokines has also begun to be analyzed in a transgenic model of B cell clonal deletion. To this end, we have administered a recombinant vaccinia virus producing human IL-2 to mice expressing an autoreactive H-2Kk,b-specific transgenic IgMk and found that IL-2 does not abrogate B cell deletion in vivo.

Expansion and clonal deletion of peripheral T cells induced by bacterial superantigen is independent of the interleukin-2 pathway.

Injection of the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB) into mice provokes a rapid expansion and subsequent contraction of the pool of SEB-reactive T cells bearing T cell receptor (TcR) V beta 8 gene products. Given that interleukin 2 (IL-2) stimulates proliferation, abolishes anergy, and counteracts apoptotic cell death in T cells in vitro, we tested whether the IL-2 synthesis inhibitor cyclosporin A (CsA) or a vaccinia virus recombinant releasing high amounts of human IL-2 modulate SEB responses in vivo. Surprisingly, neither IL-2 nor CsA were able to change the in vivo kinetics and magnitude of SEB-induced expansion, unresponsiveness to SEB, and peripheral clonal deletion of T cells expressing products of the SEB-reactive TcR V beta 8 gene family. In accord with these in vivo observations, IL-2 is incapable of reversing "anergy" and apoptotic cell death of V beta 8+ SEB-reactive T cells isolated from SEB-primed mice in vitro. Accordingly, upon SEB injection V beta 8+ T cells expand rapidly, without expressing IL-2 receptor (IL-2R)alpha chains in vivo, although SEB induces IL-2R alpha in vitro. Altogether, these results indicate that the IL-2/IL-2R-mediated pathway is not involved in T cell repertoire modulation by bacterial superantigens. Moreover, the data suggest that unresponsiveness of V beta 8+ T cells from SEB-primed mice is not a reversible process, but involves an unreversible commitment to programmed cell death. Absence or presence of IL-2 responsiveness could be a hallmark to distinguish truly reversible anergy and peripheral clonal deletion.

Cross-linking of surface IgM or IgD causes differential biological effects in spite of overlap in tyrosine (de)phosphorylation profile.

Although displaying similar amounts of surface IgM and IgD, ECH 408-1 cells only succumb to apoptosis after cross-linking of IgM (not IgD), suggesting that different signaling pathways couple to both receptors. Immunoprecipitation studies revealed the presence of several proteins selectively associated with IgM and IgD, thus ruling out that the lack of inhibitory signaling mediated by IgD might be due to membrane expression in the absence of associated proteins belonging to the B cell receptor complex. 32P metabolic labeling and immunoprecipitation studies demonstrated that IgM and IgD are associated with phosphoproteins of 32-33 kDa in an isotype-specific fashion. Kinetic analyses of tyrosine kinase activity showed that cross-linking of surface IgM or IgD resulted in the rapid (1-3 min) phosphorylation of several protein substrates on tyrosine residues, followed by a dephosphorylation step. Isotype-specific changes of the phosphorylation status specifically affected molecules in the 32-33 kDa range, i.e. IgM (not IgD) cross-linking affected a approximately 32-kDa protein, whereas IgD (not IgM) cross-linking induced phosphorylation of a protein exhibiting a slightly lower mobility (33 kDa). These results suggest that isotype-specific immunoglobulin-associated molecules could be involved in the second messenger cascade leading to different biological effects upon IgM and IgD cross-linking.

Interleukin-2: a possible trigger for autoimmunity.

High doses of recombinant interleukin-2 (IL-2) may induce autoimmune lesions in patients receiving experimental cancer treatment. In most cases, the manifestation of autoaggression is transient and organ-specific, predominantly affecting the thyroid gland. Only a fraction of the patients are concerned; most individuals (around 90%) do not develop any signs of autoimmunity. Apparently, endogenously hyperproduced IL-2 may also be implicated in the pathogenesis of autoaggression, since active phases of such disparate autoimmune diseases, like multiple sclerosis and systemic lupus erythematosus, are accompanied by elevated IL-2 serum levels. Taking into account that immunological self-tolerance is maintained by several distinct mechanisms, we investigated whether IL-2 would interfere with clonal deletion or clonal anergy in vivo. In several experimental systems, IL-2 failed to abolish clonal deletion in the murine thymus or in the peripheral T-cell compartment. IL-2 did not affect the clonal deletion of self-reactive B cells in the bone marrow either. In contrast, IL-2 was found to be effective in abrogating clonal anergy of non-deleted self-specific T cells. Only in the presence of high frequencies of self-specific, potentially autoreactive T cells, IL-2 induces autoimmune lesions. Thus, IL-2 interferes with a mechanism of self-tolerance that guarantees the inactivation of T cells that for some reason have 'escaped' clonal deletion. If these data, obtained in the murine system, are extrapolated to man, then it may be stated that the T-cell repertoire of most individuals has been completely purged from self-reactive cells. Only in the presence of a non-deleted, anergic, potentially auto-reactive T-cell population, could organ-specific disease be induced by IL-2.

Lymphoma models for B-cell activation and tolerance. IX. Efficient reversal of anti-Ig-mediated growth inhibition by an activated TH2 clone.

We have utilized several B-cell lymphomas that are growth inhibited by anti-Ig reagents as models for tolerance induction. In a previous communication, we demonstrated that the growth inhibition by anti-Ig can be partially prevented by the recombinant lymphokine, IL-4. In this paper, we report that complete protection of B lymphomas from anti-Ig was provided by a type 2 helper cell clone, D10.G4, when these T cells were activated by monoclonal anti-CD3. Conditioned medium from anti-CD3-stimulated D10.G4 cells also provided protection from anti-Ig. In contrast, little protection was observed with activated cells from a type 1 T-cell clone, A.E7. Furthermore, we show that combinations of IL-4 and tumor necrosis factors (both TNF alpha and TNF beta), as well as IL-4, effected partial protection by themselves and enhanced the activity of the other lymphokine if used in a pretreatment protocol. However, anti-cytokine antibodies were ineffective at reversing the T-cell-mediated protection. The possibility that direct T:B-cell contact mediates part of the protective signal is discussed.