{"id":143,"date":"2021-08-03T22:33:01","date_gmt":"2021-08-03T20:33:01","guid":{"rendered":"https:\/\/www.imunomed.ro\/?p=143"},"modified":"2021-08-03T22:33:01","modified_gmt":"2021-08-03T20:33:01","slug":"the-possibility-of-using-monoclonal-antibodies-anticytokine-therapy-cyclophosphamide-and-ciclosporine-in-infectious-and-oncological-pathology","status":"publish","type":"post","link":"https:\/\/www.imunomed.ro\/?p=143","title":{"rendered":"The possibility of using monoclonal antibodies , anticytokine therapy , Cyclophosphamide and Ciclosporine in infectious and oncological pathology"},"content":{"rendered":"

Abstract <\/strong><\/p>\n

Studies performed on SARS-CoV, MERS-CoV and SARS-CoV-2 have shown that many fragments of the S protein (RBD, S1<\/sub>-NTD, S2<\/sub>) could be used as targets in order to create monoclonal antibodies.<\/p>\n

The researchers identified several types of neutralizing antibodies, 3 of which have a high potential, having as \u201ctargets\u201d at least 3 linking sites on the RBD subunit of the spike protein.<\/p>\n

It is interesting to find out that some non-neutralizing antibodies, which target certain epitopes in non-RBD regions of protein S, may have a disease-enhancing effect; this may prove the involvement of cross-reactions,<\/em> the antibodies that choose unusual targets<\/em> being able to generate aberrant immune responses<\/em>. This would explain the damage of some organs: sometimes the heart and blood vessels show thrombotic (\u201cimmune-thrombosis\u201d) and nonspecific vasculitis manifestations on small and medium-sized vessels (for instance: Kawasaki disease associated with COVD-19 infection in children), haematological and possibly neurological damage.<\/p>\n

These autoimmune manifestations are also encountered in other severe viral infections; the specific character of COVID-19 infection is that the severe, fulminant forms seem to associate a special cross reactivity, possibly with a more special physical or chemical epitope or antigen, unencountered than perhaps in Sars-CoV and Mers CoV infections<\/em>.<\/p>\n

This suspected immunogen may be not only infectious, but also gaseous, even from the composition of oxygen (or chemically from the intubation cannula component), given the exacerbations registered in some patients after intubation and the reluctance to administer oxygen by intubation (it is preferable to administer oxygen from the mask).<\/p>\n

The chemical immunogenicity, if any, doubles the infectious pathology, which would explain the resistance to all types of tested therapies.<\/p>\n

Background<\/strong><\/p>\n

Normally, oxygen has tolerance in both gaseous and soluble state (bound to haemoglobin as oxyhaemoglobin), so it works like haptens. It is possible that in some patients with immune defects at the level of the BALT (lymphatic tissue associated with the bronchial mucosa), an abnormal hypersensitivity reaction is generated, more pronounced if patients are intubated; administered on the mask, the oxygen first comes in contact with the lymphatic tissue associated with the nasal and oropharyngeal mucosa which, if not defective, can better initiate the induction of immunological tolerance<\/em>.<\/p>\n

Excessive immunological reactions associated with an infectious pathology appear to have been seen also in genital staphylococcal infections in some women that used to wear menstrual tampons. Then, it was a toxicoseptic shock, evolving towards death, although sometimes the local infection was not very serious. In addition to the infectious condition triggered by staphylococcus and superantigens, it is possible that a cross-reactive immunological reaction to the cotton fibres antigens may have been added. A proof of this consists in the fact that over time, the toxicoseptic reaction in women during the menstrual period is no longer described, possibly by increasing the immune tolerance to cotton fibres.<\/p>\n

Similarly, if in some cases of COVID 19, exacerbated immunologic response reactions overlap the viral infection, there is probably a defect in the Ts lymphocyte at the BALT level that associates a defect in the macrophage, possibly related also to iron loading, because the pathology is common especially in elderly patients with cardiovascular conditions. Attempts may be made to correct this defect with Levamisole or Isoprinosine immunomodulators. Attempts in this regard have also been made in the case of chronic hepatitis, including the combination of Levamisole with Interferon. The association of Levamisole with monoclonal antibodies could be further studied.<\/p>\n

Levamisole has been tried in the treatment of chronic hepatitis in order to correct the local defect of Ts and also in the liver Kupffer cells, but did not give satisfactory results, which shows that the peripheral immune defect is doubled by a central immunological defect, at the level of thymus, which may require the association of a central correction.<\/p>\n

In infectious diseases in which an autoimmune reactivity coexists due to a suppression defect (central and peripheral), such as chronic hepatitis and probably COVID-19 infections, two major lines of the immune system are activated at the same time:<\/p>\n

– the antiviral defence line, coordinated by Th1 lymphocytes in the thymus, which leads various types of antiviral offensives, especially through Tc and NK, as well as through the non-specific immune system; in the COVID-19 infection it is described the predominant participation of Th1 and Tc lymphocytes, and from the non-specific immune system<\/strong> the activation of macrophages with increasing profile cytokines: IL-6, IL-12, TNF-alpha, interferon, to which mast cell-released factors and neutrophil are added.<\/p>\n

– the second line is the autoimmune hyperreactivity pin suppression defect (defect at the level of Ts and Tcontrasupressor, which cannot control the hyperergic reaction aberrantly occurred in some of the viral, chemical or physical antigens involved by cross reactivity. This line might be coordinated by the other Th lymphocyte involved in the majority: the Th17 lymphocyte, which may function as a regulatory T, involved in the suppression defect (should Th17 establish tolerance and send activating signals to Ts?).<\/em><\/p>\n

The proof that in some patients the two described lines are involved at the same time is the lack of therapeutic response as well as in the natural evolution of the disease. It seems that the association is difficult to overcome both by the immune system and therapy. In Covid -19 infection, the complete lack of response to corticosteroids given the existence of a mastocytic and macrophage inflammatory response is strange. In parallel, it is interesting that cortisone therapy used in the past in chronic liver inflammation had good results for a long time, although in the case the inflammation is not mastocytosis and had good results in chronic alcoholic hepatitis, where the modified self (Mallory bodies) intervenes.<\/p>\n

One explanation would be that the inducing immunogen in chronic hepatitis is more typical (viral and modified self), while in COVID 19 infection the immunogen may be more atypical, meaning that if it were viral, majorly, physically and chemically modified self, the reaction from the immune system would be strong rejection (more classic), with a favourable response to corticotherapy. Under these conditions, the modified self antigen may be at the limit, so that some Ts give it tolerance (some Th1 lines), and some lines give it rejection – possibly some of the Th17 lines (limit tolerance). When the immunosuppressive therapy is started, it probably encounters resistance from Th1 lines that have established tolerance and do not find the intervention of immunosuppressants appropriate. There seems to be a lack of coordination between these Th1 lines, which do not see what the other Th17 lines do. So, both lines seem defective, Th17 because it does not establish tolerance and does not listen to Th1, and Th1 because it does not command Th17.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 <\/em><\/p>\n

Probably in most autoimmune diseases that respond well to immunosuppressive therapy, there is concordance between the lines that drive the immune response, and in non-responders, the resistance to treatment may result from such inconsistencies between the lines involved or between central thymic coordination and peripheral coordination. In this context, it may be useful to test classical plasmapheresis in COVID-19 infection.<\/em><\/strong><\/p>\n

As a proof, in Covid 19 infection in children, multisystemic inflammatory syndrome (MIS-C) responds better to treatment because it is coordinated from the thymus. So, the thymus seems less affected and, being more developed in children, it leads to a better immune response; there are few deaths and it responds better to corticotherapy, while in adults it seems to deal more with BALT (they are more elderly with involved thymus, they have cardiovascular diseases with siderophages with high iron load); this may have led to more significant changes at the level of the alveolar macrophages ob a particular genetic field; however, one of the criteria for the positive evolution in children would be the presence of the thymus (related to central immunity), and the second would be the absence of siderophages (related to peripheral immunity).<\/p>\n

The predominance in elderly cardiovascular patients suggests the intervention of the macrophage (siderophagus) which is probably defective, which leads to an exacerbated reaction of the type IV immune system (according to the Gell Coombs classification) or close to its pattern. This exaggerated line of hypersensitivity may be driven by the T17 lymphocyte, with the involvement of the macrophage and mast cell, so it may have similarities with the immune response in tuberculosis.<\/p>\n

It is possible that in Covid 19 infection, in patients with mild forms, the immune system manages to limit the infection, using the line of antiviral defence: Th, Tc, NK, profile cytokines, nonspecific immune system. In some patients, usually in case of elderly, it seems that there is an immune defect, especially locally in the lungs; local APCs (antigen presenting cells) may not be able to properly process some of the viral antigens (or modified self or chemical antigens) and remain confined as a macrophage; this pattern is also found in tuberculosis. In tuberculosis, the antigens are of bacterial origin, and in COVD infection it is not clear which immunogens are mostly involved in the exaggerated immune response. If, in addition to viral antigenic determinants, other structures are also involved (tissue \u2013 modified self by the type of oxyhaemoglobin or non-self-exogenous, chemical or physical type of oxygen molecule), they are by cross reactivity. This would be the difference from chronic hepatitis, where viral immunogens and modified self are involved, and hence the difficulty of therapeutic approach and lack of response to corticotherapy versus chronic hepatitis.<\/p>\n

It is interesting that hepatic dialysis has proven to be effective only in some forms of hepatitis (example: acute hepatitis due to fungal poisoning), in which in addition to the toxic component an important immunological component intervenes. It is possible that a cleaning of some immunological components also took place here, so it also functioned as an equivalent of plasmapheresis<\/em>. Hence the need to perfect and expand extracorporeal cleaning techniques, including plasmapheresis in various diseases with autoimmune component, possibly in COVID -19 infection.<\/p>\n

As regards the studies on the utility of monoclonal antibodies, it should be taken into consideration that if a hypersensitivity or cross-reactivity reaction is involved, the humoral disorder confirms this: Ig M antibodies appear later and are more nonspecific, so they are not used much in anti-infective defence, mostly Ig G, which can be useful in diagnosis. Antiviral immunity appears to be more cellular than humoral, which would explain the differences in results between neutralizing monoclonal antibodies used in vitro and in vivo.<\/p>\n

Neutralizing monoclonal antibodies have good antiviral effects in vitro (they neutralize infection of cells in cultures); however, in vivo it appears to be under the control of the immune system, which has as its first line of defence the cell line and not the humoral line.<\/p>\n

Probably all immunomodulatory medication administered in any condition is evaluated by the central immune system according to its effects, even if the drugs are haptene-type. This would explain the differences in the effect of some immunomodulators, depending on the status of the immune system: in the case of Cyclophosphamide, in autoimmune diseases, the status of the immune system is a decrease in exaggerated reactions, so, Cyclophosphamide goes hand in hand with higher Th commands and the immunosuppressive effect is maximum. In neoplasms, at least at onset, the upper lines induce commands to increase immunity and how long these lines resist, the patients do not have immunosuppression; under these conditions, Cyclophosphamide can be administered in large doses and, not going hand in hand with the commands of the main lines, does not cause such strong immunosuppression, because theoretically it could not be used at these doses in oncology.<\/p>\n

If the salt of the immune system really matters when administering the immunomodulator, then studies related to Cyclophosphamide could be expanded and the effect more closely evaluated in patients with immune hyperreactivity, in normal patients, in patients with immune hyperstimulation under conditions of a neoplastic pathology or even infectious. Several specialists have hypothesized regarding the extension of treatment with Cyclophosphamide in infectious pathology associated with hyperergic reactions.<\/p>\n

It would also be possible to expand the search for secondary antigenic determinants, which induce non-neutralizing antibodies and which can be immunogenic and involved in cross-reactivity without being highly pathogenic (in terms of infectivity).<\/p>\n

In Covid-19 infection, some non-neutralizing antibodies which target epitopes from non-RBD regions of the protein S may have a beneficial effect precisely because these epitopes may be immunogenic and their blocking may decrease the immune response.<\/p>\n

Classic neutralizing monoclonal antibodies, which block the virus directly, may block most sites in the main RBD regions, reveal sites in non-RBD regions, and the autoreactive immune system becomes more aggressive in these non-infectious epitopes. This would explain the effectiveness of treatment only in severe cases, where the autoimmune reaction is maximal and death-causing and where blocking with neutralizing antibodies can be attempted. In mild and moderate cases probably one of the mechanisms is the one mentioned above; here they are not used because they probably increase humoral and possibly cellular reactivity. Then perhaps in these cases it would be useful to combine neutralizing antibodies with non-neutralizing monoclonal antibodies, non-RBD.<\/em><\/p>\n

Another treatment idea would be to modulate Ts with Levamisole before or at the same time with monoclonal antibody therapy.<\/p>\n

In conclusion, several broad directions of immunological therapy can be described in COVID \u2013 19 infection:<\/p>\n

– anti-infective therapy aimed at increasing the Th\/Tc cell line, given that it seems to be mostly involved in antiviral defence (and in tuberculosis, the immunity is predominantly cellular and the antibodies are not so effective in diagnosis or therapy). In this case, we should discuss various immunostimulatory therapies that have been tried in acute respiratory infections, indeed in mild and moderate infections, not in severe ones (immunomodulators such as Luivac, Bronhovaxom, Polidin have been used successfully).<\/p>\n

– the second line majorly involved is that of hypersensitivity; the proof is that most cases heal spontaneously, so the immune system has the ability to annihilate the coronavirus alone, and it does not seem too high pathogen (the size of the Koch bacillus or HIV, after the high percentage of remissions and coronavirus). Some authors discuss two types of strains, with high pathogenicity (high Covid 19) and with low pathogenicity. However, microbiologists did not identify significant differences and the epidemiological context also matters, for instance in the same community severe cases coexist with mild cases. It seems more likely that some patients have a genetic immunological defect but, of course, more aggressive viral strains may overlap in these patients. The necroptic anatomo-pathological examination does not focus mainly on necrosis or typical signs of infectious lesions that cause death, nor on thrombotic or vasculitic aetiology, so it is possible that the death may occur through the exaggerated reaction of immunological hypersensitivity.<\/p>\n

Hypersensitivity reactions can be not only type IV, in which the prototype would be the stimulation by viral epitopes (possibly blocked at the level of the APC \u2013 antigen presenting cells), with the generation of angry macrophages involving cytokines and profile mediators and with the participation of the mast cell; type II may also be involved in Gell Coombs classification: antibody-mediated, cytotoxic-cytolytic with antigens associated with the cell or matrix, in which an important role is played by opsonic phagocytosis. Antigens can be part of the modified self by the action of the virus or an exogenous, chemical or physical agent (possibly oxygen). The type I reaction does not appear to be involved due to the lack of response to corticotherapy, and the type III reaction is not obvious (absence of circulating immune complexes at significant titres, complement dosages).<\/p>\n

Any immunomodulatory therapy introduced into the body would be preferable to be in accordance with the Th coordinator commands, otherwise there is a risk of obstruction.<\/p>\n

In this context, it seems that anti-TNF-alpha and anti-IL-6 anti-cytokine therapies are more effective in rheumatic diseases – most of the therapies used are antireceptor and not anti-cytokine; the immune system more readily accepts antireceptor therapies, which do not affect its coordination and does not receive therapies with high impact on molecules or coordination signals or on higher lymphocytes (Th, Tc). Corticotherapy is one of the most valuable acquisitions of immunology that goes more on the lower lines, less and only at high doses on the upper lines.<\/p>\n

The lack of response to corticotherapy in Covid-19 infection suggests trying other immunosuppressive medications or monoclonal antibody therapies, with one of the goals being to \u201ctarget\u201d other cellular or humoral lines responsible for the manifestations of the disease and resistance to treatment.<\/p>\n

Indeed, if the immunogen involved in cross-reactivity is gaseous, so more particular than the usual infectious, chemical or self-modified antigens, the autoimmune response may be atypical, as may some of its effectors, cells or molecules.<\/p>\n

Thus, the main cytokines described to be involved (IL6, IL12, TNF alpha), being addressed to a more specific antigen (recognized as non-self), may have a slightly different structure from the classical ones (isomorphic), thus resulting a weak response to classical anticytokinic therapy.<\/p>\n

It should be noted that in all types of therapies, antireceptor therapy prevails and antichytokinic therapy is not very effective, probably because the immune system does not agree with too many interventions on its status, especially in signal modulation. Proof of this is Cyclosporine and more of Tacrolimus, which have not been shown to have a satisfactory in vitro effect in autoimmune diseases precisely because they aim too high and too strong at the upper lines of the immune system, which is probably a type of self-regulation that does not accept major external interventions. Hence the need to review treatment with calcineurin inhibitors and other immunomodulatory therapies, including anticytokine therapy. It should be noted that Tacrolimus could only be used in transplantation, and Cyclosporine has indications only in a few diseases.<\/em><\/strong><\/p>\n

In Covid-19 infection, cytokine antireceptor therapy, especially of the IL-6 antireceptor (Tocilizumab, which is one of the most potent cytokine receptor blockers), did not provide results in rheumatology, suggesting that there may be changes at the IL-6 level and receptors (isomorphisms); the experienced anti-cytokine therapy was the classic one, created for a more arthritic inflammatory autoimmune pathology in which the central role is played by ragocyte<\/em><\/strong>; In COVID-19 pneumonia, the pulmonary macrophage may be loaded with iron (siderophagous<\/em><\/strong>); this could have repercussions on the activity and on the synthesis of the products. Probably if the iron load is higher, the deviation from normal is more pronounced: the proof is the severity of the reaction in cardiovascular patients and the elderly; also, children have less frequent and less severe forms, more systemic.<\/p>\n

It is possible that in children, the form of central autoimmunity predominates, with the absence of intrathymic deletion of autoreactive clones (MIS-C), while in adults and the elderly there is more local form with TS defect at BALT and macrophage by iron loading.<\/p>\n

In the case of plasmapheresis in myasthenia gravis, it is addressed exclusively to myasthenic crises and in systemic lupus erythematosus only to those resistant to classical treatment and\/or high titres of circulating immune complexes. It would be preferable for plasmapheresis to be used outside of myasthenic seizures and other forms of lupus, but it is probably only possible in forms in which variants of modified autoantibodies or cytokines (isomorphs) are involved.<\/p>\n

Immunosuppressants have also been studied as combination therapy in infectious pathologies with components of immunological hyperactivation, and some authors have recently proposed the use of Cyclophosphamide in inflammation associated with COVID-19 infection.<\/p>\n

The literature cites the case of a young patient with glomerulonephritis treated with Cyclophosphamide, who overlapped with a COVID-19 infection (positive tests and computed tomography examination: \u201cground glass opacities\u201d). Cyclophosphamide may have attenuated severe pulmonary manifestations.<\/p>\n

In chronic hepatitis B virus (HBeAg negative), corticosteroids or even potent immunosuppressants such as Azathioprine with beneficial effects have been given in the past. Only after a large number of years of use the effect was reversed, recording viral activation which caused it to stop. It is possible that the history of glucocorticoids repeats itself in COVID-19 infection, which can be used as a supportive treatment under supervision until there are signs of inefficiency or danger. It is interesting to study when and why the effect of Prednisone was reversed in chronic viral hepatitis.<\/p>\n

In Japan, a ten-year-old child with a lung abscess with Mycoplasma pneumoniae and paraclinical markers of hypercytokinemia received adjuvant treatment with Cyclosporine as an immunomodulator.<\/p>\n

As regards the immunosuppressive treatment, clinical studies and observations from transplant immunology (especially renal) have shown that calcineurin inhibitors could be used in COVID-19 infection, without increasing the severity of the infection (in vitro).<\/p>\n

Cyclosporine may have a protective role (in vitro, it appears to function as an antiviral agent: Cyclophilin A binds Nsp-1 (non-structural protein 1) identified to the SARS-CoV nucleocapsid.<\/p>\n

However, no concentration (nor inhalation) could be established in vitro to satisfy this desideratum (antiviral or immunomodular).<\/p>\n

Cyclosporine is among the most potent inhibitors of the Th lymphocyte, the main cytokine used by it, IL2 and the Tc lymphocyte. However, the observations are valid in vitro. It is possible that the effect is too strong and is addressed to higher commands, and the immune system does not accept influences at a higher level, especially since Th and its main interleukin, IL-2, are involved. The same goes for Tacrolimus, which is 10 to 100 times more potent than Cyclosporine and is used only in transplantation.<\/p>\n

The Th lymphocyte, which is the leader of the immune system, appears to have the highest resistance to immunosuppressants (including Cyclosporine and Tacrolimus) compared to other lymphocytes.<\/p>\n

This could also be explained by the fact that the Th lymphocyte has a maximum of self-protection: it never comes in contact with pathogens directly, but only through APC (antigen presenting cells). Also, the regulation is done primarily by itself, autocrine, by self-secretion of IL-2, so it does not receive much influence from anyone, neither from other elements of the immune system nor from outside. Engst launched this idea of \u200b\u200bself-protection by autocrine secretion of IL-2<\/em> since 1984. The Th lymphocyte can coordinate the Ts lymphocyte, can stimulate or inhibit it as needed, but not the other way around: the Ts lymphocyte, in intercellular cooperation, when it receives signals to induce suppression from Th, it responds positively and also emits signals and suppressive molecules antero and maybe retrograde. However, it probably cannot emit stimulatory or control signals on the Th lymphocyte, which results in a higher level of the Th lymphocyte, which confirms its \u201cgeneral\u201d role.<\/p>\n

This immunological \u201cisolation\u201d and leadership role would be one of the explanations for the Th resistance to both immunosuppressive and immunostimulatory medication (most immunostimulators can easily influence nonspecific immune cells, NK cells and B lymphocytes, but cannot influence the Th in vivo<\/em>. Several immunostimulants used in neoplastic and infectious pathology have described effects of increasing Th lymphocyte activity, but this is probably only in vitro. It would be desirable to improve the stimulation and coordination of the Th\/Tc line, possibly by finding antigens that stimulate well the APC line, (thus T-dependent). Immunostimulators with weaker action may have more independent T stimulation, on the B lymphocyte line.<\/p>\n

Also, the increased resistance of the Th lymphocyte appears to allow the use of vaccines in acute infections, including attempts to administer the hepatitis B vaccine in chronic hepatitis. More extensive studies on Th lymphocytes could expand the scope of immunostimulators.<\/p>\n

Potent vaccines, such as pyocyanin preparations, are likely to have Th stimulation by processing in APC; however, after a while most vaccines decrease their effectiveness because they probably remain only with a simpler humoral stimulation and non-specific immune system, more NK, macrophage – polymorphonuclear, complement. It is interesting the evolution of immunostimulators such as mushroom extracts, using in oncology which initially had high potency, (probably had the same Th stimulation which subsequently decreased, because dendritic cell activation is described in antimicrobial immunity); the route of oral administration may also be important: MALT (lymphatic tissue associated with the digestive tract) initially\u00a0 showed good reactivity, possibly by spreading spores in the general population, in newer patients with MALT destroys them too strongly.<\/p>\n

A more standardized formula, closer to conventional vaccines (possibly parenteral), may be more useful, with which the immune system is accustomed in the sense that it has „exercises” through standard childhood immunostimulations.<\/p>\n

It is not known in oncology how to capture and process neoplastic antigens at the APC level and they may not be taken up by the APCs and may not be presented to the Th lymphocyte, as this would trigger a strong rejection response from the tumour cells since the onset of neoplasia. So probably the immune defect in neoplasms is major, it is present from the beginning and is more related to the specific immune system, to the cooperation of APC\/Th lymphocyte. It seems that the defect is more at the level of Th, Ts, T counterpressor and APC lymphocytes and less at Tc, with blockage at the level of specific immunity, while nonspecific immunity works more normally: NK cells play the main role and therefore can be considered that they are part of the specific immunity; they seem to take the lead in oncology, overcoming Th and Tc. Macrophages have phagocytic and secretory functions and it would seem that they cannot function as APCs, because it is not described in the literature to take over and process neoplastic cells, but only modified somatic cells, which have become antigenic. Also, receptors for neoplastic antigens are not described, but only receptors for antigens from modified somatic cells (scavenger receptors, class A superfamily, involved in apoptosis, homeostasis, clearance). Otherwise, the nonspecific immune system participates with all the variable elements in the antineoplastic defence.<\/p>\n

Genetic determination of NK lymphocytes is also important; as the disease progresses, their number decreases in the final stages. One of the explanations would be that Th and Ts take measures to suppress the non-specific immune system precisely because Th, being defective, does not find the intervention of the non-specific immune system opportune and gives commands to Ts to suppress it. This would be a proof that Th, Ts and Tcontrasupressor do not see the neoplastic cells, so they have a major defect, or have established from the beginning a total tolerance to these cells, which resembles that of pregnancy; only the other cells react, so they did not establish tolerance: NK lymphocytes, B-lymphocytes probably T independent (antibody secretion is inefficient), complement, macrophages, polymorphonuclear cells. Some experts have advanced the idea that neoplastic cells are covered by antibodies, however it seems more like a load on them that is from the in situ stage, from the first cell appeared. If it is an electromagnetic charge that resembles the egg cell, it could trigger a signal of induction of tolerance as in pregnancy, through an unknown mechanism, that of inducing the load tolerance, which of course is triggered from the egg cell. If the first neoplastic cell accidentally carries the same signal (electromagnetic?) as the egg cell and embryonic cells, this could explain the lack of tumour rejection.<\/em><\/strong><\/p>\n

NK cells also play a central role in pregnancy rejection pathology, especially at the placental level.<\/em><\/strong><\/p>\n

Another piece of evidence that Th lymphocyte has established tolerance to neoplastic cells is the ineffectiveness of vaccines that use dead tumour cells.\u00a0\u00a0 <\/em><\/strong><\/p>\n

 <\/p>\n

Cyclophosphamide<\/em><\/strong> (Cy), is an alkylating agent that chemically reacts with the nucleophilic centres of DNA, RNA or lymphocyte protein molecules, thus causing the decrease or inactivation of immune-functions. Depending on the dose, it can be immunosuppressive, theoretically it can be anti-inflammatory or it can completely suppress the immune response, being of choice in allogeneic STEM cell transplantation and other types of transplantation.<\/p>\n

At low doses Cyclophosphamide can be immunostimulatory by inhibiting T regulator (Treg: CD4 + CD25 + Foxp3) and some Ts lines (acting in the early stages of the immune response). The effect has been shown in some animal and human studies with neoplasms (example: metastatic colorectal cancer). This property resembles one of the actions exerted by the vaccination of BCG (Mycobacterium tuberculosis vaccine) on the Ts lymphocyte (stimulation by lymphocyte inhibition).<\/p>\n

In tumours, subsets of T regulatory highly activated are highlighted (Highly suppressive Treg cells), which express a multitude of receptors and have a maximum cytokine secretion (especially IL 10), which must be repressed; in contrast, other subset of T reg are expressed in autoimmune diseases, with generally low numbers and low receptor density and other immunomodulatory uptake filings that should be activated. They could be involved in resistance to treatment.<\/p>\n

In conclusion, if the immunomodulation at Th level is more difficult to achieve due to its resistance, immunomodulation at Treg or Ts level can be tried both in terms of stimulation (Levamisole) and inhibition by various immunomodulatory doses (Cyclophosphamide, BCG vaccine). Studies could also be extended to the field of anti-infective or anti-neoplastic immunostimulants.<\/p>\n

The effects of Cyclophosphamide differ primarily in dose timing. In addition, timing is important as well as the cadence of administrations.<\/p>\n

At low doses: 50 mg\/day (or 50 twice a day), the researchers in oncology obtained the effect of amplifying the anti-tumour response mainly by inhibiting Treg.<\/p>\n

The effect on Treg is transient (it regenerates in about 10 days).<\/p>\n

The most sensitive to Cyclophosphamide are Treg cells and some Ts lines (which enter the early stages of the immune response), NK cells, B lines and CD8 lines are depressed from 200mg\/m. The most resistant are the CD4 lines (resist up to 600mg\/m) and some Ts lines.<\/p>\n

The immunological profile induced by low doses is usually:<\/p>\n

– Treg inhibition (and some Ts lines) which results according to some authors the activation of macrophages simultaneously with the increase of CD8 + effectors, the production of IFN-.gamma and granzymes B;<\/p>\n

– B lymphocyte deletions, which would not affect immunity too much.<\/p>\n

– NK inhibitions – cell<\/p>\n

– Tc: CD8 + resists<\/p>\n

– Th: CD4 + resistance; this resistance goes up to 600 mg\/m2<\/sup>;<\/em><\/strong> from this dose, Th begins to be depressed (the dose has been determined by administering Cyclophosphamide from 50 to 700 mg\/m2<\/sup>, increasing every 3 weeks (Hengst, 1984). It also appears that CD4 cells recover faster than CD8.<\/p>\n

– As an immunosuppressant, the effective doses also seem to be the lowest, 100mg\/day. It is interesting that at the beginning of immunosuppressive therapy the doses were even higher, between 50 and 150 mg\/day (1.5-3 mg\/kg\/day), some authors indicated in 1998 also average doses of 5 mg\/kg\/day up to high doses of 7 mg\/kg\/day 7-10 days up to a maximum of 3000 mg.<\/p>\n

The same 50 mg\/day doses that have been used in autoimmune diseases as immunosuppressants have recently been experienced as immunostimulants in colorectal cancer studies. At doses of 50 mg\/day administered experimentally in colorectal cancer, the researchers obtained an increase in the antitumor effect, probably mainly by inhibiting Treg. One explanation would be that in the two processes (autoimmune and tumour) the lines of the immune system are expressed differently:<\/em><\/p>\n

– in the case of autoimmune diseases, the most competent Th lymphocytes initiate commands to suppress the exaggerated immune response and slow it down. In these cases, the administration of immunosuppressants goes hand in hand with the higher commands of the immune system and the effect is maximum. In some auto immunities, the therapeutic effect is not obtained because probably several such drainage lines are inconsistent and may be contradictory or do not match the suppression commands established from the central level with those from the peripheral level. It is also possible that the Covid-19 infection in which the commands instituted by Th1 do not agree with the commands instituted by Th17, which leads to a blockade at the level of effectors and non-therapeutic response. This would probably be one of the explanations for the resistance to treatment in some auto immunities. They may respond to plasmapheresis, which means that plasmapheresis may purify this type of effector.<\/em><\/p>\n

– In the case of neoplasms, at least at the beginning the upper lines of the immune system, an antitumor stimulation is initiated and they can counteract the immunosuppressive effect of Cyclophosphamide, resisting up to high doses.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 <\/em><\/p>\n

The effect on Th CD4 + – resistance; this resistance goes up to 600 mg\/m2<\/sup>, according to Hengst\u2019s 1984 studies, which administered doses between 50 and 700 mg\/m2 <\/sup>with increases at 3 weeks; it is not known exactly on which batches the experiment was performed, but it seems that this is the threshold and this would explain the possibility of using high doses of this type in oncology: 400-1000 mg\/m2<\/sup>. Patients tolerate these doses and usually do not relapse or suffer from a second neoplasia, so resist some Th lines that, coordinating on Tc, support immunity and survival.<\/em><\/strong><\/p>\n

The effect of Cyclophosphamide seems to differ depending on both the dose and the condition in which it is used:<\/em><\/strong><\/p>\n

– in autoimmune diseases, up to the threshold dose, immunosuppression seems to be induced by affecting the other lines and not the upper Th and is more effective. When the level of action on upper Th lymphocytes is reached, blockages and inefficiency also occur, so it cannot be used as an immunosuppressant in higher doses. The same goes for Cyclosporine and Tacrolimus, the dose should not be tested so as not to affect too much Th to optimize the effect.<\/em><\/strong><\/p>\n

– in neoplasms, only high doses are given for the same reason, and, being another immunological status, the resistance is high.<\/em><\/strong><\/p>\n

– in transplantation, the immunological status of the recipient may be previously normal and the Th resistance is high, so it is likely that the threshold for inducing immunosuppression is higher and differs in the three indications.<\/em><\/strong><\/p>\n

All these data prove that the immune system has the ability and intelligence to direct its own effector lines as well as those induced therapeutically according to needs.<\/p>\n

 <\/p>\n

Mihaela Ghimpu
\nClinical immunology specialist
\nand allergology<\/p>\n

 <\/p>\n

\u00a0 References <\/strong><\/p>\n

1 Bara\u00a0 C. , Esential de imunologie\u00a0 ,Editura\u00a0 ALL , 2002<\/p>\n

2 Blidaru I.E. , Elemente de imunologie gesta\u021bional\u0103, Institutul European, 2007.<\/p>\n

3 Carasevici E. ,Dumitriu I. ,Cianga C. ,Cianga P.,\u00a0 ,,Zugun-Eloae F. ,Imunologie , Universitatea de Medicina \u0219i Farmacie\u00a0 Gr.T .Popa Iasi\u00a0 1999 .<\/p>\n

4 Channappansvor, Perman S.\u00a0 F.Pathogenic human coronavirus ifections :causes and conse\u00a0 quences of cytokine storm and immunopathology . Semin Immunopathol. 2017 jul; 39(5):529-539-PMC-Pub Med<\/p>\n

5 Codreanu\u00a0 C., Ionescu R. Predeteanu D ,Rezus E. ,Parvu M, Mogosan C . Popescu C.C, , Rednic S . , Recomand\u0103ri SRR :Managementul pacientilor cu boli reumatice \u00een contextul COVID-19\u00a0 , Via\u021ba Medicala\u00a0 Nr 26,3iulie 2020<\/p>\n

6 Cojocaru M. , Autoimunitatea \u00een schizofrenie , Via\u021ba\u00a0 Medicala Nr . 20 ,20 mai 2011<\/p>\n

7 Cojocaru .M\u00a0 , Autoanticorpii \u0219i boala Alzheimer , Via\u021ba Medicala Nr 51 , 18 decembrie 2009<\/p>\n

8 Covic M., \u0218tef\u0103nescu D., Sandovici I., Gorduza E.V.: Genetic\u0103 Medical\u0103, Edi\u021bia a-III-a, Editura Polirom, 2017.<\/p>\n

9 Cristea V., Costin N., Crisan M., Olinescu A.: Imunologie clinic\u0103 , Ed. Casa C\u0103r\u021bii de \u0219tiin\u021b\u0103 ,Cluj-Napoca, 1999.<\/p>\n

10 Dejica D.: Tratat de imunologie clinic\u0103 ,Ed. Dacia ,Cluj-Napoca,1997.<\/p>\n

11 Dobrescu D., Dobrescu L., Negres S., McKinnon R.: Memomed, Literatura Universitar\u0103 ,Bucure\u0219ti ,2019.<\/p>\n

12 Felsenstein S., Herbert J. A., McNamara. P. S., Hedride C.r. COVID-19 :Immunology and tratment option . Clin. Immunol 2020 Jun ; 215:108448. Doi :10 . 1016\/y.clim.2020.108448 Epus 2020 Apr.27PMID : 32353634 Free PMC article.<\/p>\n

13 Gologan R. Manifestari autoimune asociate bolii .Viata Medicala Nr 37 , 18 septembrie 2020 .<\/p>\n

14 Gologan .R .Noi aspecte privind infectia COVID-19 .Coagulopatia-un comportament atipic . , Via\u021ba Medicala\u00a0 Nr 37 , 18 septembrie 2020<\/p>\n

15 Ghioca ,\u00a0\u00a0 Anticorpii Ig G COVID-19 ,mai probabil dup\u0103 14 zile de simptomatologie . Via\u021ba Medicala Nr 27 , 10 iulie\u00a0 2020<\/p>\n

16 Hugher E., Scurr M., Campbell E.,James E., Godkin A., Gollimore . T-cell modulation by Cyclophosplamide for tumord therapy. Immunology. 2018 May ;154(1) :62-68. PMC-Pub Med.<\/p>\n

17 Ionescu.\u00a0 F. Vaccinuri candidate pentru COVID-19,, Via\u021ba Medicala Nr 23 , 12 iunie 2020<\/p>\n

18 P\u0103unescu V., Tatu C.A.,St\u0103nescu D.I.,Medrea D.P.: Imunologie Concepte Fundamentale \u0219i Aplicative, Editura Hericon, Timi\u0219oara, 1996.<\/p>\n

19 Pere\u021bianu D., Saragea M.M.: Imunologia \u00een teoria \u0219i practica medicinei ,vol. II ,Ed. All, 1998.<\/p>\n

20 Popescu I. Gr.: Alergologie: fiziopatologie ,diagnostic ,tratament, Ed. All, 1998.<\/p>\n

21 Poulsen N.N., , Albrecht von Brunn , Hornum M. ,Jensen M. .B., Cyclosporine and COVID-19: Risk or Favorable?, Am J . Transplant , 2020 Nov ;\u00a0 20(11) : 2975 -2982. doi : 10 .11111\/ajt 16250 .Epub 2020Sep7<\/p>\n

22 Revannasiddaiah\u00a0 S , Kumar Devadas\u00a0 S\u00a0\u00a0 , Palassery R , Kumar Pant N\u00a0 , Maka V.V , Med Hypotheses 2020Nov\u00a0 ; 144: 109850 .doi : 10.1016 \/ j.mehy.2020.109850. Epub2020May23<\/p>\n

23 Restian A. , Marile dileme ale pandemiei de COVID-19 ., Via\u021ba Medicala Nr . 32 , 14 aug 2020.<\/p>\n

24 Restian A. , Leg\u0103tura dintre SARS -CoV-2 \u0219i bolile asociate , Via\u021ba Medicala Nr .25, 26 iunie 2020.<\/p>\n

25 Rizescu. B. R.: Agenda medical\u0103 \u201998, Ed. Medical\u0103 ,Bucure\u0219ti,1998<\/p>\n

26 Schot T. S. , Kerckhoffs A. P. M. , Hilbrands .L.B.\u00a0 R. J. Van M arum , ImmunosupppresivDrugs : A Review , Front Pharmacol 2020 Aug 28 ; 11.333.doi\u00a0\u00a0\u00a0 10.3389\/ fphar 2020. 01 333 : 1<\/p>\n

27 Scurr M , Pembroke T , Bloom A , Roberts D , Thomas A , Smart K, , Bridgeman H.\u00a0 . Adams R , Brewster A , Jones R Gwynne\u00a0 ,S ,Blount ,Harrop R.,Hills, Gallimon, Godkin. A. Low- Dose Cyclophosphamide Induces Antitumoral T Cell Responses ,which Associatewith Survival \u00een Metastatic Colorectal Cancer ; Clin . Cancer Res , 2017 Nov 15 23 (220 ;67716780 doi : 10 1158 \/ 1078-0432<\/p>\n

28 Simache A, Dexametazona , promi\u021b\u0103toare \u00een tratamentul COVID-19 , Via\u021ba Medicala\u00a0 Nr.25,26 iunie 2020,<\/p>\n

29 Simache A. , Recunoasterea sindromului inflamator multisistemic , vitala pentru copiii cu COVID-19 .Via\u021ba Medicala ,Nr\u00a0 37 , 18 septembrie 2020<\/p>\n

30 Stroescu V., Chira C., Ignat P., Moise A., Cancea P., Oprian D.,Rizescu R., Stoicescu Gh., \u0218u\u021beanu St.: Agenda medical\u0103 ,Bucure\u0219ti ,1994.<\/p>\n

31 Taylor R., Paulman P. M. ,\u00a0 Paulman A.A. , Harrison J . D.,Nasir L .S. ,Jarzynka K. J.\u00a0 , Manual de diagnostic diferential , editura ALL 2016 .<\/p>\n

32 Udristioiu A.\u00a0 , Ttratamentul cu anticorpi plasmatici anti SARS CoV 2, speran\u021ba \u00een tratamentul COVID -19 , Via\u021ba\u00a0 Medicala Nr . 31 , 7 august 2020<\/p>\n

33 Voiculescu C., P\u0103tr\u0103\u0219canu A., Voiculescu M., Hongeag M., Avramescu C., V\u00e2lcea V., Radu E.: No\u021biuni de imunologie \u0219i imunopatologie ,Ed. Academiei Rom\u00e2ne,1999<\/p>\n

34 Wooding J , , Bach H , , Treatment of COVID-19 with convalescent plasma lessons from part coronavirus outbreaks\u00a0 , Clin microbiol infect 2020 oct : 26(10)1436-1446<\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

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