Homeopathic Cyclosporin: Taming the Immune Response Using Isopathic Methodology

Homeopathic Cyclosporin: Taming the Immune Response Using Isopathic Methodology

By Narender Kumar Mathur MD, Ram Kumar Gulati MD

Abstract:
Coronavirus disease of 2019 (Covid-19) infection has exposed the lack of sufficient understanding of the immune processes of human body responsible for optimum antiviral action. With conventional medicine proving less than adequate in taming the virus, it is quite possible that homeopathy, acting on the subcellular level, may be better suited to facilitate in vivo immunological responses against SARS Cov2. Based on the current understanding of our immune system, encouraged by a previous experiment showing in vitro stimulation of lymphocytes with homeopathic dilutions of Cyclosporin and constructing on the basic homeopathic tenet of Similia similibus curentur, but applying it on the immunological level too, we propose that homeopathic form of Cyclosporin should be examined as a potential candidate to fight Severe Acute Respiratory Syndrome Coronavirus 2 (SARS Cov2). Lower potencies of Cyclosporin should help in reversing the initial immunosuppression and likely prevent the consequent uninhibited immune dysregulation that causes cytokine storm.

Introduction
Covid19 is the name ascribed by the World Health Organization (WHO) to the pandemic illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS Cov2)¹. It is an enveloped, single stranded, positive sense RNA virus, around 29.9 kb in length, 65–125 nm diameter, belonging to genus betacoronavirus, family Coronaviridae²,³.

SARS Cov2 virus has four major structural proteins—spike (S), envelope (E), membrane (M) and nucleocapsid (N), 16 non-structural proteins (1–16 nsp) and 5–8 accessory proteins. S protein is needed for attachment, fusion, entry and transmission into the host cell⁴. It uses the ACE2 receptor to enter the host cell. S1 subunit of S protein has two domains—N terminal domain (NTD) and C terminal domain (CTD), the latter also called receptor binding domain (RBD). RBD is responsible for the first interaction with the host cell receptor causing conformational change in S2 leading on to membrane fusion. Protein cleavage between S1 and S2 is mediated by the transmembrane serine protease 2 (TMPRSS2). Once inside the cell, the infecting RNA acts as a messenger RNA (mRNA), this is then translated by host ribosomes to produce the viral replicative enzymes. After replication and sub genome RNA synthesis, the S, E and M viral structural proteins are translated and inserted into the endoplasmic reticulum (ER), and subsequently moved into endoplasmic reticulum-Golgi intermediate compartment (ERGIC). There, N protein encapsulates viral genome and buds into a membrane containing ERGIC to form mature viruses, which are transported to the cell surface in vesicles and released by exocytosis⁵,⁶.

ACE2 receptors in humans are found in the heart (endothelium of coronary arteries, myocytes, fibroblasts, epicardial adipocytes), vessels (vascular endothelial cells and smooth cells), gut (intestinal epithelial cells), lungs (tracheal and bronchial epithelial cells and type 2 pneumocytes, macrophages), kidneys (luminal surface of tubular epithelial cells), testes and brain⁷. ACE2 is highly expressed in oral mucosa⁸. The ACE2 gene is expressed on X chromosome and increased expression has been found in Asians⁷. The SARS Cov2 virus attaches to the ACE2 receptors on the host. Severe Acute Respiratory Syndrome Coronavirus (SARS Cov) also attaches on the same receptor and both viruses share approximately 80% genome sequence homology. However, compared to the latter, the former has more atomic interactions to the receptor increasing the affinity by 10–20 folds⁹.

Pathophysiology of SARS Cov2¹⁰,¹¹
SARS Cov2 infection usually stays asymptomatic over the first few days when a decrease in innate immune responses and reduced expression of ACE2 in upper airways can be seen. Over the next few days upper airways and conducting airways are affected and reduction in T cells is evident. Eventually in some clients, the infection reaches the lower airways causing hypoxia with lungs showing ground glass infiltrates and ARDS-like picture. Alveolar type 2 cells are destroyed either directly by virus or undergo apoptosis. With reduction in type 2 cells, there is a reduction in production of type 1 pneumocytes too. Type 1 pneumocytes are responsible for gas exchange while type 2 are responsible for production of type 1 cells and surfactant. Eventually severe fibrosis ensues. The elderly seem to have increased viral load due to reduced immune function and reduced ciliary response of the airways.

Initial infection shows increased total white cell count. Coronaviruses seem to be able to evade the innate immune response, suggested by their longer incubation period of 2–14 days when compared to 1–4 days of influenza virus¹². Decreased secretion of interferons and TNF alpha leads to dampening of immune cells recruitment and therefore leads to unabated viral replication¹³. This later on leads to increased release of proinflammatory cytokines like TNF alpha, IL-1 beta, IL-2, IL-6, IL-8, Interferon gamma induced protein 10 (IP10), IFN gamma induced protein 1 and macrophage inflammatory protein 1alpha leading to lung damage. This cytokine storm can lead to significant inflammatory pulmonary damage, with some clients meeting a fatal end. Pneumocytes, macrophages and dendritic cells all contribute to cytokine production. Studies of SARS Cov showed inflammation being mediated by pathogen recognition receptors (PRR) like TLR3, 7 and 8, and also by retinoic acid inducible gene I and NOD like receptor.

Clients with severe Covid-19 exhibit marked lymphopenia. Chen Y et al. used immunohistochemistry and immunofluorescence to characterize hilar and subscapular lymph nodes and spleens post-mortem from six clients who died from Covid-19¹⁴. In addition to splenic and lymph node atrophy and necrosis, the authors reported significant lymphocytic apoptosis. Of note, ACE2-expressing CD68+CD169+ macrophages were detected in the splenic marginal zone and in marginal sinuses of lymph nodes, and these macrophages contained SARS-CoV-2 nucleoprotein antigen and showed upregulation of IL-6. Virally infected tissues also showed higher expression of FAS. This suggests that CD169+ macrophages could contribute to viral spread, excessive inflammation and activation-induced lymphocytic cell death during SARS-CoV-2 infection. Secretion of cytokines including TNF-α, IL-6, and IL-10 was increased in Covid-19 clients. Interestingly, the numbers of total T cells, CD4+ T and CD8+ T cells are negatively correlated to levels of TNF-α, IL-6, and IL-10, respectively, suggesting these cytokines may be involved in the decrease of T cells detected in Covid-19. T cells are possibly decreased and exhausted¹⁵.

CD4 and CD8 cells tend to show a decline even before chest X-ray changes are seen. Viral particles are seen inside peripheral blood T cells, liver, spleen and lymph nodes. T cell decrease may be secondary to direct viral effect causing cell lysis, Fas-Fas ligand interaction or TNF related apoptosis-inducing ligand signaling axis. Studies with MERS showed that disease progression seemed to be associated with a skewing towards Th2 immune response and recovery was associated with enhanced Th1 response, which may be true for SARS Cov2 too¹⁶. Viremia after pulmonary involvement can result in viral sepsis. Metabolic acidosis may be associated with microcirculation dysfunction. A large number of deaths in Covid-19 clients had evidence of disseminated intravascular coagulation. Increase in D-dimers or other fibrin degradation products are associated with poor prognosis.

The condition is also characterized by high ferritin, akin to macrophage activation syndrome (MAS), catastrophic antiphospholipid syndrome, septic shock or reaction to anti CD28. These hyperferritinemic conditions are also characterized by a cytokine storm with increase of IL1, IL6, IL17 etc and mortality approaching 50%. The H chain of the ferritin may be involved in activating macrophages. Soluble CD163 (sCD163) is a marker of macrophage activation and may be used as a marker of cytokine storm¹⁷. High NLR (Neutrophil:lymphocyte) ratio is prognostic marker for severe infection¹⁸,¹⁹.

Recovery of the immune system is quicker in mild cases with T cells showing improvement in 15 days and almost normalizing in 25 days. However in clients who died, the T cells kept on decreasing till the end. We still don’t know if neutralizing antibodies function well and how long they last. There seems to be a difference between total measurable antibodies and protective neutralizing antibodies. 10–20 percent of symptomatic clients have little or no measurable antibodies; whether this signifies mild infection or inhibition of immune response by a strain is unknown. Most hospitalized clients show IgM response by day 9 and then IgG response by two weeks, the latter coinciding with the disappearance of the virus²⁰. It’s still unclear how long the protective immunity would last after the infection.

It’s clearly evident that Covid19 is characterized by initial immunosuppression which subsequently, in some clients, paves the way to a cytokine storm likely due to uninhibited dysregulation of the immune system which is not able to control itself. With conventional medicine not providing a concrete answer to how SARS Cov2 moulds the immune system to its advantage, it may be prudent to explore the complementary medical system. Homeopathic philosophy, Similia similibus curentur, suggests that when a toxic substance is given in dilutions (potentised form), it brings cure for the toxic effects it produces, or some other toxin with similar effects produces, when given in crude form. Cyclosporin-A or Cyclosporin is one such molecule which produces immunosuppression and has similarities to SARS Cov2 infection.

Cyclosporin
Cyclosporin (a toxic substance in larger doses) is a homodetic cyclic-11 hydrophobic peptide isolated from the fungal species Tolypocladium Inflatum gams²¹. It binds to the eight stranded antiparallel beta barrels structured cyclophilin and the prolyl isomerase substrate binding site is coincident with the Cyclosporin binding site. Cyclosporin-cyclophilin complex then binds to calcineurin contributing to immunosuppression produced by Cyclosporin²².

Cyclophilins play a key role in the lifecycle of many coronaviruses, including human coronaviruses 229E (HCoV-229E) and NL-63 (HCoV-NL63), feline infectious peritonitis coronavirus (FPIV), SARS-CoV and Middle-East Respiratory Syndrome coronavirus (MERS-CoV). Cyclosporin A (Cyclosporin), a potent cyclophilin pathway inhibitor, blocks the replication of various coronaviruses in vitro, including HCoV-229E, HCoV-NL63, FPIV, mouse hepatitis virus (MHV), avian infectious bronchitis virus, and SARS-CoV. However, Cyclosporin cannot be used in clients with Covid-19 because of its strong immunosuppressive properties²³. However, by virtue of the aforementioned homeopathic principle, dilutions of Cyclosporin should help reverse initial immunosuppression and thereby may mitigate the toxic effects of Covid19 immune dysregulation.

Cyclosporin and SARS Cov2 — Analogy (Conforming to principle of similia similibus curentur)
Both Cyclosporin and SARS Cov2 lead to lymphopenia and suppression of innate immune responses. Cyclosporin can promote superantigen mediated cell death in CD4+ lymphocytes²⁴. Generation of suppressor cells and reversal of TH:TS ratio is seen after Cyclosporin therapy²⁵. Cyclosporin directly interferes with antigen presenting function of macrophages²⁶.

SARS Cov2 clients present with lymphopenia causing reduction in CD4, Treg, Th1 and CD8 cells²⁷. Also, the cytokine storm of proinflammatory cytokines—IL-6, TNF alpha, IL-1B, C-reactive protein suggest a superantigen component of the virus²⁸.

Cyclosporin can directly inhibit the activation of B-lymphocytes to a variety of stimuli by interfering with Ca++ dependent signals²⁹. Lun et al (1991) have shown that along with inhibiting B cell activation, Cyclosporin may also decrease or increase the differentiation and immunoglobulin production by B cells, depending on the antigen used³⁰. By suppressing CD4 numbers, Cyclosporin has indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). B cells probably contribute to the cytokine storm in Covid19 by producing IL-6, as one case series showed that clients with agammaglobulinemia developed only mild symptoms while those with Common Variable Immunodeficiency showed significant severity³¹.

Natural Killer (NK) cell activity is only mildly impaired under normal Cyclosporin therapeutic dose³². However, a dose dependent inhibition of NK cell activity is noted when NK cells are exposed in vitro to Cyclosporin³³. Zheng et al (2020) showed that the total number of NK and CD8+ T cells was decreased markedly in clients with SARS-CoV-2 infection³⁴. The function of NK and CD8+ T cells was exhausted with the increased expression of NK group 2 member A receptor (NKG2A) in Covid-19 clients. As an inhibitory receptor, NKG2A has been demonstrated to induce NK cell exhaustion in chronic viral infections. Importantly, in clients convalescing after therapy, the number of NK and CD8+ T cells was restored with reduced expression of NKG2A. These results suggest that the functional exhaustion of cytotoxic lymphocytes is associated with SARS-CoV-2 infection. Hence, SARS-CoV-2 infection may break down antiviral immunity at an early stage.

Apart from an effect on the immune system, the effects on the various body organs show similarity too. The primary organs of involvement in SARS Cov2 infection are the lungs causing damage to the alveoli leading on to the cytokine storm. Cyclosporin therapy may lead to ARDS and it’s believed that high concentration of Cyclosporin in the pulmonary vasculature causes a localized ‘capillary leak’ or it may be an idiosyncratic reaction to Cyclosporin³⁵,³⁶.

Both Cyclosporin therapy and Covid19 infection are associated with nervous system afflictions. Cyclosporin can lower seizure threshold, can enhance viral induced T cell mediated demyelination and has been associated with demyelinating polyneuropathy, Guillain-Barre syndrome and Parkinsonism³⁷–⁴³. Cyclosporin therapy is also associated with a dose dependent toxic myopathy characterized by myalgias, muscle weakness or rhabdomyolysis⁴⁴. A variety of neurological manifestations have been described in SARS Cov2 infection including encephalopathy, encephalitis, Guillain-Barre syndrome, myelitis, rhabdomyolysis and acute cerebrovascular events⁴⁵.

Cyclosporin, similarly produces renal side effects, but in a dose dependent manner, including tubular changes (isometric vacuoles, inclusion bodies, microcalcifications), striped interstitial fibrosis and more seriously, focal and segmental glomerulosclerosis⁴⁶–⁴⁸. Covid19 has been associated with acute kidney injury, proteinuria, hematuria and collapsing glomerulopathy⁴⁹.

Cyclosporin therapy is related to the development of a syndrome resembling thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). Probable mechanisms include defective synthesis and release of prostacyclin from endothelial cells and excessive platelet aggregation due to increased utilization of high molecular weight multimers of factor VIII, whose levels are raised after vascular injury induced by Cyclosporin⁵⁰–⁵⁵. Covid19 may be associated with coagulopathy and may resemble HUS/TTP or DIC⁵⁶.

Cyclosporin induces a dose dependent decrease in serum and intratesticular testosterone levels and produces impairment of testicular spermatogenesis, steroidogenesis, epididymal sperm maturation and fertility in rats⁵⁷. There has been increasing evidence that SARS Cov2 infection is likely associated with male genital damage. As we know that testes have high expression of ACE2 receptors, they are a likely target for the virus. One study found significantly increased LH with significantly decreased testosterone:LH and FSH:LH ratios in a study of 81 male clients affected with Covid19⁵⁸.

Cholestasis, manifested by increased levels in serum bilirubin, alkaline phosphatase and gamma-glutamyl transferase, is the most frequent manifestation of Cyclosporin hepatotoxicity⁵⁹,⁶⁰. It is dose dependent and is often associated with a variable component of cholangitis and pericholangitis. Covid19 has been associated with hepatic dysfunction, particularly in those with severe disease. Liver dysfunction includes increase in transaminases and even acute hepatic injury. It may be multifactorial including roles of direct viral cytopathic effect, immune mediated or secondary to sepsis or drugs⁶¹.

Evidence indicates that Cyclosporin has a direct toxic effect on pancreatic islet cell functions, leading to impaired insulin synthesis and secretion⁶². Hyperglycemia has been noted in a significant number of Covid19 clients and it has been speculated that SARS Cov2 may enter islets causing acute beta cell dysfunction⁶³,⁶⁴.

Cyclosporin produces glutathione deficiency and the resultant oxidative stress contributes to its hepatotoxicity and nephrotoxicity⁶⁵. Glutathione, glutathione precursors (N-acetylcysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-κB and addressing “cytokine storm syndrome” and respiratory distress in clients with Covid-19 pneumonia⁶⁶.

Selenium is an important component of glutathione peroxidase, which is depleted in Cyclosporin treated individuals and its supplementation seems to prevent the vascular toxicity⁶⁷. Sodium selenite, but not selenate, can oxidize thiol groups in the virus protein disulfide isomerase rendering it unable to penetrate the healthy cell membrane. In this way selenite inhibits the entrance of viruses into the healthy cells and abolishes their infectivity⁶⁸.

Homeopathic Cyclosporin
Use of homeopathic potentized form of Cyclosporin has previously been studied in vitro where lymphocytes from mice sensitized with Salmonella antigens (live or inactivated) when incubated with the homeopathic form of Cyclosporin showed increase in inositol phosphate 3, intracellular calcium, increased phosphokinase C, increased production of IL-2 & gamma IFN (Th1) and increased production of IL4 (Th2) and increased TNF-alpha⁶⁹. Safety of the drug was tested by using three potencies i.e., 30, 200 and 1000 in albino mice by oral route once a day for three months whereby no change was observed in the behavior, weight, and food intake. Autopsy did not reveal any gross abnormality in liver, kidney, thymus, spleen, and lymph nodes (routine histology). When lymphocytes from two HIV-1 infected clients (CD4 count 400 to 500) were incubated with this drug, an increase in lymphocyte counts was observed, with no obvious adverse effects. Dr. Sudhir Gupta, USA and Dr. N K Ganguly, Professor and Head, Department of Experimental Medicine, PGI, Chandigarh, India provided the laboratory support during these previous experiments. These in vitro experiments show that homeopathic form of Cyclosporin has the potential to stimulate lymphocytes. It is possible that reversal of initial immunosuppression may suffice to inhibit the subsequent cytokine storm, as it is quite likely that removal of some deterrent by the immunosuppressed state is probably the cause of uninhibited cytokine storm which then damages the self to a much greater extent than what the virus ever does. Lower potency of drug is likely to reverse immunosuppression without subsequent hyperstimulation or aggravation.

We know that classical homeopathy is based on looking at similarity between symptom complex of the client and that produced by the remedy on healthy volunteers, we have tried taking the concept to the pathological and molecular level, using isopathic methodology and with a hypothesis that similarity in the latter micro-environment may follow homeopathic principles too.

The notion to use Cyclosporin in Covid19 developed after studying similarities between toxic effects of Cyclosporin and HIV in late 1990s. (Mathur NK, Bhargava P. Immunosuppression—Bliss or curse: Tale of two poisons. Indian J Sex Transm Dis 1998; 19: 1-21) (accessible at nkmathur.com/immunosuppression-bliss-and-curse-a-tale-of-two-poisons/)

Considering the similarities and construction on the tenet of Similia similibus curentur, Cyclosporin in low homeopathic dilutions should help in reversing the initial immunological immunosuppression and likely prevent the subsequent immune dysregulation that leads to the cytokine storm. Pilot in vitro studies on mice using a few potencies of the drug showed encouraging results.

Conclusion
Covid-19 infection has exposed the lack of complete understanding of the immune processes of the human body responsible for optimum antiviral action. With conventional medicine proving less than adequate in taming the virus, it is quite possible that homeopathy, acting on the subcellular level, may be better suited to facilitate in vivo immunological responses against SARS Cov2. Based on the current understanding of immune system and previous in vitro experiment showing potential of Cyclosporin in homeopathic dilutions to stimulate lymphocytes, we propose that homeopathic form of Cyclosporin should be examined as a potential candidate to fight the current pandemic, which is raging relentlessly, despite the best of scientific efforts.

We should consider further proving homeopathic Cyclosporin to be able to add more symptoms to what we currently have in our materia medica.

Reference Works application, using Marsh’s Clinical Drug Pictures, currently lists some symptoms of the remedy as confusion, headaches, convulsions, hypertension, pancreatitis, vomiting, diarrhea, thrombocytopenia, hemolytic anemia, immunosuppression and increased susceptibility to infections, muscle weakness and burning sensations of hands and feet, to name a few.

In this article, though we rely on the isopathic method for treatment, we also advocate that with further provings, we may be able to prove a classical use of the remedy in Covid cases, and other future forms of SARS related illnesses, as well.

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