& Homeostatic Agents


Editor-in-Chief: Professor Pio Conti, Immunology Division, University of Chieti-Pescara, 66013 Chieti, Italy. E-mail:


JBRHA Vol 20, Issues 1 & 2, 2006


1. Prolonged statin administration does not act on the cell-mediated immunity of HIV-infected dyslipidemic patients treated with a steady and effective highly active antiretroviral therapy. A two-year prospective study of statin versus fibrate administration, versus a dietary/exercise program


pp 1-9

R. Manfredi, L. Calza, F. Chiodo

Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Bologna

-Alma Mater Studiorum-, S. Orsola Hospital, Bologna, Italy


Objective. To assess whether statin administration for HIV-associated hyperlipidemia has

long-term effects on immune recovery (as expressed by the trend of mean CD4+ lymphocyte count), in

patients on a virologically-active HAART regimen since 12 months or more. Methods. Single-centre,

open-label, prospective study of 301 hyperlipidemic patients treated with statins (99 cases, with a

predominant hypercholesterolemia), fibrates (116 subjects, when hypertriglyceridemia prevailed), or a

isolated dietary/exercise program (86 patients, used as a control group). Neither epidemiological nor

clinical, virological, or immunological differences were detected among the three study groups at

baseline. During the subsequent follow-up, patients were excluded from evaluation should virological

efficacy was not maintained, and/or initial hypolipidemic therapy was modified or interrupted for any

reason. Results. The quarterly assessment of mean CD4+ lymphocyte count did not disclose any

statistically significant difference among the three study groups, since baseline and until at least 24

consecutive months of follow-up. Our data tend to exclude relevant in vivo negative activities of

statins on immune system recovery of HIV-infected individuals who undergo a virologically effective

HAART treatment. Conclusions. Multiple, pleiotropic features have been attributed to both statins and

fibrates, and also apparently significant effects on laboratory markers of HIV disease progression

have been recently claimed or expected. Despite some preliminary in vitro and ex-vivo models, both

the main hypolipidemic classes administered for the management of HIV-related dyslipidemia (both

statins and fibrates) do not seem to act significantly on clinical immune response of patients

successfully treated with HAART. Multifactorial pathways are expected to interact with the cellmediated

immune system of HIV-infected patients undergoing successful HAART, and further studies

are needed to elucidate whether more subtle immune effects might be prompted by a long-term

administration of hypolipidemic drugs in this speciasl setting.



2.  Genetic disregulation of TNF alpha and TNF alpha type II receptors in colon cancer at the II and III

stage of disease

pp 10-14

M. Muc-Wierzgoń, E. Nowakowska-zajdel, T. Kokot, A. Kozowicz, A. Wiczkowski ¹, E.

Grochowska-niedworok ², U. Mazurek ³, J. Wierzgoń 4.


Department and Teaching Ward of Internal Medicine, Silesian Medical University, Bytom, Poland

¹Department of Biology, Silesian Medical University, Poland

²Department of Human Nutrition, Silesian Medical University, Poland

3Department of Biochemistry, Biopharmacy and Molecular Biology, Faculty of Pharmacy, Silesian Medical

University, Sosnowiec , Poland

4Department of Surgery, Centre of Oncology, M.Curie-Sklodowska Memorial Institute, Branche Gliwice,


It was analysed the expression of the genes coding TNFalpha and TNF RII receptors (TNF RII:

TNFR2 membrane and soluble domain, TNFR2/R7 soluble domain) in colon cancer at the II and III

stage of disease, by estimation mRNA expression. The study included 80 patients with

histopathologically confirmed adenocarcinoma. The number of TNFalpha mRNA, TNFR2 mRNA and

TNFR2/R7 mRNA copies were estimated in tumour and healthy tissue. The highest number of mRNA

TNFα copies were investigated in all samples of tissue and independently of the stage of disease.

Simultaneously we noticed the largest number of mRNA copies for TNFalpha and TNF R2/R7 in healthy cells at the III stage of disease.It is possible to draw a hypothetical line separating the anti-cancer activity of TNFalpha and its influence on cancer progression.





3.  Rantes potentiates human macrophage aggregation and activation responses to calcium ionophore (A23187) and activates arachidonic acid pathways


L.N. Shanmugham, C. Petrarca1, M.L. Castellani1, S. Frydas 2, J. Vecchiet 3, P. Conti 1, S. Tete’ 4


Department of Radiation Oncology, HARVARD University, Medical School, Boston, USA

1University of Chieti-Pescara, Immunology Division, Medical School, Chieti, Italy

2Aristotelian University, Parasitology Department, Thessaloniki, Greece

3Division of Infectious Diseases, Medical School, Chieti, Italy

4Dental School, University of Chieti, Italy


ABSTRACT. Regulated on activation, normal T-cell expressed and presumably secreted (RANTES),

which generally mediates monocyte-macrophage (MO) activation and recruitment, is a protein of 8-10

kD that chemoattracts eosinophils, monocytes and certain T leukocyte subsets. RANTES is coded for

by a gene cluster located on human chromosome 17 and is a human T-cell specific molecule. RANTES

is a member of a beta intercrine subfamily reported to be a selective chemoattractant for human

monocytes rather than neutrophils, and is also a chemoattractant for memory T lymphocytes, CD4+

cells. RANTES is a modulator of many important macrophage functions in addition to aggregation,

such as chemotaxis and phagocytosis. Our investigations focussed on the ability to modulate the

aggregation of macrophages induced by calcium ionophore A23187. The ionophore A23187 directly

induced potent aggregation of MO which was markedly enhanced when the cells were pretreated with

RANTES. However, the addition of RANTES in the absence of other co-stimuli did not directly induce

aggregation. Additional cytokines examined for possibly inducing macrophage aggregation were

interleukin-1 (IL-1), tumor necrosis alpha (TNF-α), and IL-6; all proved to be incapable of inducing

aggregation directly, nor did they enhance the effects of A23187 on macrophage aggregation.

Additionally we found that RANTES can directly stimulate MO to activate specific pathways of

arachidonic acid cascade, inducing a synthesis and release of thromboxane (TxA2) and leukotriene

B4 (LTB4). RANTES did not augment the potent ability of A23187 to induce increased production of

LTB4 or TxA2 by human MO. These data suggest that RANTES can contribute directly to monocyte-

MO leukocyte-activation during inflammatory responses, resulting in greater cell aggregation,

activation, and specific pro-inflammatory arachidonic acid products release, such as TxA2 and LTB4.



4. T cell selection and differentiation in AIDS disease: the model of HIV-discordant monozygotic twins

Pp 24-28

C. Agrati, c. Gioia, f. Soldani, f. Martini, a. Antinori, f. Poccia


National Institute for Infectious Diseases -L. Spallanzani-, IRCCS, Rome, Italy


ABSTRACT. The model of monozygotic twins has been repeatedly studied to control the genetic and

age-specific effects on HIV disease. Focusing on this natural model, the expression of CD27/CD45RA

differentiation markers and the distribution of the Vβ TCR repertoire was analyzed on CD4+ and CD8+

T cells. In our HIV-discordant monozygotic twins, a significant reduction of naļve T cells and a parallel

accumulation of effector/memory T cells was induced by HIV infection, as well as a skewing of T cell

repertoire evidenced by VβTCR analysis. The block of HIV replication by highly active antiretroviral

therapy (HAART) restored most of the T cell maturation and selection process, with some exception

among CTL differentiation and repertoire. Altogether, the model of HIV-discordant monozygotic twins

is a valuable tool showing that HAART is not able to completely restore the CTL profile.



5.  Cancer chemotherapy-induced lymphocytosis: a revolutionary discovery in the medical oncology



P. Lissoni1, L. Fumagalli2, F. Brivio2, F. Rovelli1, G. Messina1, G. Di fede3, M. Colciago4, G. Brera5


1Division of Radiation Oncology, Milan, Italy

2Division of Surgery, S.Gerardo Hospital, Monza, Milan, Italy

3Institute of Biological Medicine, Milan, Italy

4Laboratory of Analyses, Hospital of Carate, Carate, Milan, Italy

5Ambrosian University, Milan, Italy


ABSTRACT. The recent advances in the investigation of tumor immunobiology have suggested that

cancer chemotherapy, in addition to its well known cytotoxic activity, may play modulatory effects on

the endogenous production of cytokines involved in the control of both tumor angiogenesis and

antitumor immunity. Cancer chemotherapy constantly acts with inhibitory effects on anti-bacterial,

anti-viral and anti- mycotic immune responses, whereas its action on the anticancer immunity, which

is mainly mediated by lymphocytes, has still to be better investigated and defined. The present study

was carried out to evaluate the influence of chemotherapy on lymphocyte count and its relation to the

clinical response in cancer patients suffering from the most commonly frequent tumor histotypes,

including lung, colorectal, breast and prostate carcinomas. The study included 144 consecutive

metastatic solid tumor patients. Lung cancer patients were treated with cisplatin plus gemcitabine,

colorectal cancer patients received oxaliplatin plus 5-fluorouracil, while those affected by breast

cancer or prostate carcinoma were treated with taxotere alone. An objective tumor regression was

achieved in 66/144 (46%) patients, whereas the remaining 78 patients had only a stable disease (SD)

or a progressive disease. Independently of tumor histotype and chemotherapeutic regimen, a

lymphocytosis occurred in patients who achieved an objective tumor regression in response to

chemotherapy, and lymphocyte mean count observed at the end of the chemotherapeutic treatment

was significantly higher with respect to the values seen before the onset of treatment.On the contrary,

lymphocyte mean number decreased on chemotherapy in patients with SD or PD, even though the

decline was statistically significant with respect to the pre-treatment values in the only patients who

had a PD in response to chemotherapy. This study would suggest that chemotherapy itself may

paradoxically act at least in part as a cancer immunotherapy by inducing lymphocytosis, as well as

previously demonstrated for the only immunotherapy with IL-2, probably by modulating the cytokine

network and correcting the altered endogenous production of cytokines, responsible far cancerrelated



6.  Immunophenotypic peculiarities of mobilized stem (CD34+) cells in blood from patients with severe spinal cord injury

Pp 36-40


N.N. Tupitsyn 1, V.N. Yaryghin 2, A.S. Bryukhovetskiy 3, L.Yu. Grivtsova 1, G.L. Mentkevich 1,

I.S. Dolgopolov 1, A.Yu. Zaitsev 3, M.I. Davydov 1


1 State N.N.Blokhin Russian Cancer Research Center Affiliated to the Russian Academy of Medical Sciences, Moscow, Russian Federation

2 Russian State Medical University, Moscow, Russian Federation

3 NeuroVita Clinic of Restorative Interventional Neurology and Therapy, Moscow, Russian Federation


Immunophenotype of mobilized stem blood cells (CD34+) was studied in 29 patients with

late post-traumatic spinal lesions. The CD34+ cells demonstrated different levels of expression of

CD45, CD38, monomorphic determinants HLA-DR and gp130 epitopes. Most patients presented with a

CD34+ cell fraction with no or low expression of common leukocytic antigen CD45. Only 2 patients had

>15% of HLA-DR-CD38- cells in the CD34+ fraction. A common transducer molecule of interleukin-6

family cytokines gp130 was expressed on stem (CD34+) cells in all the cases, 26% of the patients had

an activated gp130 phenotype, i.e. a combination of C7+ and A1- epitopes.



7. Interleukin -1beta (IL-1 beta), interleukin –6 (IL-6) and tumor necrosis factor (TNF) in plasma and pleural fluid of pneumonia, lung cancer and tuberculous pleuritis


G. Ilonidis1, E. Parapanisiou 2, A. Anogeianaki 3, I. Giavazis1, E. K. Theofilogiannakos3,

P. Tsekoura1, K. Kidonopoulou1, Chr. Trakatelli4, Z. Polimenidis2, P. Conti5, G. Anogianakis2


1Fourth Internal Medicine Clinic, Hippokration Hospital, Aristotle University of Thessaloniki, Greece

2Department of Immunology and Histocompatibility, Hippokration Hospital, Aristotle University of Thessaloniki, Greece

3Laboratory of Experimental Physiology, Aristotle University of Thessaloniki, Greece

4Department of Internal Medicine, G. Genimatas Hospital, Thessaloniki, Greece

5Immunology Division, University of Chieti, Italy


ABSTRACT. Interleukins IL-1β, IL-6 and TNF are increased in plasma of patients with severe infections

and septic shock. Our objective was the evaluation of IL-1β, IL-6 and TNF in plasma and exudates of

pleural fluid and their contribution to the diagnosis. We studied 44 patients, 27 men and 17 women

with mean age 66.81 ± 11.75 years; 16 with pneumonia and parapneumonic effusion, 14 with primary

lung cancer and pleural effusion and 14 with tuberculous pleuritis. We measured IL-1β, IL-6 and TNF

in serum and pleural fluid with ELISA. In patients with pneumonia and parapneumonic effusion the

mean value of IL-1β IL-6 and TNF in plasma was 9.05, 19.24 and 21.34 pg/ml and in pleural fluid 10.34,

32.19 and 25.30 pg/ml. In patients with lung cancer the mean values of IL-1β, IL-6 and TNF were 5.33,

11.74 and 11.51 pg/ml and 6.70, 13.13, 20.89 pg/ml, respectively. In those with tuberculous pleuritis the

respective mean values were 10.33, 49.94, 21.27 pg/ml and 14, 56.59, 23.58 pg/ml. In conclusion, IL-1β

and IL-6 were found increased in plasma and tuberculous pleural fluid, indicating an inflammatory