Graves' Disease after Interleukin-2 Therapy in a Patient with Human Immunodeficiency Virus Infection

Abstract

Interleukin-2 (IL-2) is a cytokine that regulates the proliferation and differentiation of lymphocytes, and is currently used clinically in the treatment of assorted malignancies. Additionally, IL-2 is being actively investigated in clinical trials for treatment of human immunodeficiency virus (HIV) infection. Patients treated with IL-2 are susceptible to autoimmune thyroid disease (AITD), presenting as thyroiditis, which leads to either thyrotoxicosis or hypothyroidism, if not correctly and promptly identified and treated. IL-2-induced hypothyroidism can also sometimes follow a thyrotoxic phase. However, the development of Graves' disease (GD) in this clinical setting has not been reported to date. Here, we report the case of a 39-year-old HIV-infected man in whom GD developed after IL-2 therapy. We correlated the immunologic parameters pertinent to the patient's HIV infection status with clinical, hormonal, and serologic evidence of GD during its emergence. This revealed an association between peripheral blood cell numbers of specific lymphocyte subpopulations (CD4(+), CD3(+)CD25(+), and naïve T-cells) and serum levels of markers for AITD (free thyroxine [T(4)] and thyroid-stimulating immunoglobulin). Interestingly, no association was found between natural killer (NK) cell numbers and AITD markers. The immunopathogenesis of GD in this patient may be similar to that hypothesized for the GD that occurs in immune-reconstituted patients after combination antiretroviral therapy. From a practical standpoint, we propose that patients who have received or are receiving treatment with IL-2 who show signs of hyperthyroidism need to be carefully evaluated for GD.

Graves' Disease as a Manifestation of Immune Reconstitution in HIV-Infected Individuals after Initiation of Highly Active Antiretroviral Therapy

“…After this period, naive CD4 T-cell numbers slowly improve as a result of repopulation and new thymic production. Graves' disease may also be associated with Interferon Alpha (IFN α ) used to treat hepatitis C and Interleukin 2 (IL-2) therapy in the setting of HIV [3, 9]. Earlier studies found that TPO antibodies and TSH receptor antibodies appeared after CD4 T cells had dramatically increased on HAART, whereas they were repeatedly absent prior to HAART [7].…”

“…However, a minority of patients might experience a paradoxical clinical decline as a result of immune restitution [2]. This phenomenon occurs by virtue of restoration of the capacity to mount an inflammatory response against both infectious and noninfectious antigens [3], hence the term immune reconstitution inflammatory syndrome (IRIS). IRIS occurs most commonly as a result of reactivation of infections such as Mycobacterium avium complex, Mycobacterium tuberculosis , Cryptococcus neoformans, or cytomegalovirus and tends to occur between a few weeks and several months after initiating HAART, corresponding with CD4 positive memory cell repopulation [4].…”

Thyroid Function Abnormalities in HIV-Infected Patients

“…Some studies suggest the CD4 cells increase in a biphasic pattern after HAART initiation, with initial redistribution of memory CD4 cells from lymphoid tissue followed, months later, by expansion of naive CD4 cells [44]. Consistent with this explanation is the observation of transient Graves' disease among HIV-infected patients with naive CD4 cell expansion driven by IL-2 treatment [45]. However, delineating the timing and pattern of cell types in CD4 cell reconstitution remains an area of ongoing research [46].…”

Integrated non‐invasive system for quantifying secreted human therapeutic hIL2

“…Human interleukin-2 (hIL2) is a natural polypeptide hormone, which has a key role in activating a network of immune responses within the body (Kaplan et al, 1992;Yamaguchi et al, 2003). The critical role of hIL2 has led to clinical trials for the treatment of several deadly diseases, including cancer (Bubenik, 2004;Eklund and Kuzel, 2004;McDermott and Atkins, 2004;Porta, 2006;Stroncek et al, 2005) and AIDS (Jacobson et al, 1996;Jimenez et al, 2004;Martin et al, 2005;Smith et al, 1999). The clinical efficacy of hIL2 makes it an appropriate therapeutic protein for development of usage in biohybrid organs.…”