Thymalin.

Introduction

Thymalin is an immunomodulator polypeptide derived from the thymus. This basic polypeptide is made up of 38 amino acids residues. Studies have shown that this immunomodulator molecule does occur naturally in the thymus. A summary of studies and findings concerning the functions on the thymus are described below.

Thymus

It is a specialized bilobed secondary lymphoid organ which is critical to the development of functionally active and self-tolerant T-cells. It is also a component of the adaptive immune system. Studies have shown that the actions of the thymus are mediated by immunomodulators.

In the thymus, the precursor thymocytes do develop into mature T-cells. The process of maturation involves recombination and rearrangements of the gene segments that code for the T-cell receptor. This leads to the development of unique peptide: MHC (Major Histocompatibility Complex) combinations of the receptor and this mediates central tolerance. These T-cell receptors mediate antigen recognition and antigen presentation. The mediation is occurs through interactions between epitopes of an antigen and the corresponding paratopesof the T-cell receptor.

The process of gene rearrangements is prone to errors which could lead to the development of either non-functional T-cells or T-cells which react strongly to self-antigens (autoreactive T-cells). To prevent these errors from occurring, the developing T-cells undergoselection based on their T-cell receptors affinity and specificity. Functional T-cells undergo positive selection and the autoreactive T-cells undergo negative selection. This occurs in the central medulla of each lobe of the thymus.

The mature T-cells eventually enter into the general circulation where they constitute the T-cell repertoire which mediates the functions of the adaptive immune system. Normally, the normal T-lymphocyte population is achieved early in life and this leads to involution of the thymusin early adulthood. However, loss (or sometimes complete absence) of the thymus before these population thresholds are reached results in DiGeorge Syndrome which is characterized by severe immunodeficiency.There is still residual T-celllymphopoiesis throughout the adult life. Nonetheless, studies have shown that complete involution of the thymus in old age is associated with increased susceptibility to severe infections and cancer development. This has been attributed to immune deficiency which impairs the immune response to infections and impairment of immune surveillance against tumors.

Other diseases associated with thymic dysfunction are allergic hypersensitivity, Severe Combined Immunodeficiency Syndrome (SCID), lymphomas, Myasthenia Gravis, thymomasand the rarity APECAD(Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy).

Thus, it is evident from the studies carried out on the thymus that the inductive environment provided by the thymus leads to the development of a functional, self-tolerant T-cell repertoire.

Thymic immunomodulators have the potential of restoring the integrity of thymic activity in a dysfunctional or diseased thymus, thus treating the associated immune deficiency or managing its severity. One of the most potent and efficacious pharmaceutical preparation of thymic immunomodulators is Thymalin.

Pharmacology of Thymalin

It is based on the principle that natural peptides have a significantly high potential of restoring normal biologic activity and are also associated with an acceptable toxicological profile. Studies have shown conclusively that the biologic activity is restored by the active component of the drug (the polypeptide constituent) while the toxicological profile is usually associated with the vehicle used.

In Thymalin, the active component is apolypeptide, and the vehicle used is a combination of water-soluble salts. Studies have shown that the immunostimulant effects of Thymalin are due to the capability of the polypeptide to modulate the ratio of the subpopulations of functional immunocompenent cells.

Specific studies

The studies which are reviewed below are known to have provided conclusive findings, and as such, their findings do have a bearing on the clinical use of Thymalin as an immunomodulator agent.

1.      Thymalin and thymus factor.

One of the earliest studies done on the immunomodulatory potential of thymicderivatives was done in 1982 by Pisarev et al in a study titled“Isolation, Physico-Chemical and Biological Properties of the Immunity Polypeptide Biomodulator from Thymus”. The study aimed at isolating a polypeptide fraction from the thymus which would be able to stimulate immunogenesis; and then evaluating its composition and its biological, physical and chemical properties in order to identify its corresponding thymic equivalent. The study used a multi-component extract which was subjected to fractionation procedures to derive three fractions labeled 1, 2 and 3, which were then analyzed for immunobiological activity. Also, the respective molecular masses and isoelectric potentials of the fractions were measured. The tyrosine contents of the fractions were also measured using the Lowry method. The results showed that fraction 1 exhibited no immunobiological activity. Fraction 2 and Fraction 3 both showed immunobiological activities, with fraction 3 showing a more efficacious immunostimulatory activity profile.  Fraction 3 was christened Thymalin and its conformational structure and properties elucidated. Thereafter, it was introduced into a culture of lymphocytes derived from pseudo-operated and thymectomized guinea pigs. The results showed a significant increase in the lymphocyte population derived from thymectomized guinea pigs, while there was no discernable increase in the lymphocyte population derived from the pseudo-operated guinea pigs. When thymus factor was introduced into a similar culture, the results obtained were similar to that obtained from Thymalin, and thus the study concluded that Thymalin is was indeed the thymus factor.

2.      Thymalin and Cervical Carcinoma.

In 1984, Dekster conducted a clinical study entitled “Clinico-immunologic changes in patients with cervical cancer after treatment with Thymalin” whose aim was to evaluate the beneficial effects of Thymalin on immunosuppressive states. In the study, 50 cervical carcinoma patients were evaluated. These patients registered low lymphocyte counts of variable severity before the administration of Thymalin. After Thymalin administration, the lymphocyte populations were measured and they were found to have increased significantly with the patients registering normal or near- lymphocyte counts. Thus, the results of this study demonstrate the need to includeThymalin in the management plans of cervical carcinoma.

3.      Thymalin and Endometrial Hyperplasia

In 1989, Zaporozhan et al conducted a study entitled “Effect of Thymalin on the immunological indices and morphofunctional structure of the uterus in guinea pigs with endometrial hyperplasia” which was aimed at evaluating the anti-neoplastic effects of Thymalin. The female guinea pigs studied numbered 125 in total, and the endometrial hyperplasia was induced by synestrol administration. The parameter used to monitor the progress of the indicated pathology was the lymphocyte population. This population decreased as the hyperplasia worsened. The administration of Thymalin in the diseased subjects resulted in the normalization of immune system indices (that is, restoration of the lymphocyte population to within the normal reference range), and partial restoration of the endometrial morphology.

Thus, from the above three studies, it can be concluded that Thymalin acts through the thymus to restore both the quantitative and qualitative capacities of T-cell lymphocytes. It also shows that Thymalin can be used in the management of various cancers.