RESULTS

CD4⁺ Lymphocytes Increase and CD8⁺ Lymphocytes Decrease in Response to α₁PI Replacement Therapy

To examine the interrelationship between α₁PI concentration and CD4⁺ lymphocyte numbers, data were examined from a blinded study conducted to monitor hematologic changes following weekly infusions of α₁PI (60 mg/kg) in 11 individuals with genetic α₁PI deficiency (PI_zz) who had never before received α₁PI therapy.

Two HIV-1 patients, Alpha and Beta at different stages of disease (Table 1) received weekly infusions of 120 mg/kg α₁PI augmentation. Two additional HIV-1 patients, Gamma and Delta, with apriori evidence of abnormal immune status received the same therapy. The ability of Gamma to respond to antigen was impaired (positive PPD followed by negative PPD), and Delta exhibited systemic inflammation. Finally, 2 non-HIV-1 patients were included in the study, PI_zz-1 and PI_zz-2, who manifested normal numbers of CD4⁺ lymphocytes and a diagnosis of emphysema in the context of genetic α₁PI deficiency. The PI_zz patients received half-dose weekly infusions of 60 mg/kg α₁PI augmentation. Patients Delta and PI_zz-2 were included only in CD4⁺ lymphocyte functional analyses (see Methods).

HIV-1⁺ patients Alpha, Beta, and Gamma (Fig. 1) and both PI_zz patients (not depicted) responded to therapy with an initial burst of lymphocytes. After 2 wks of therapy, patients Alpha and Beta achieved normal numbers of CD4⁺ lymphocytes with increases from 297 to 710 and from 276 to 393 cells/pl, respectively.

OiAntitrypsin Therapy Increases CD4⁺ Lymphocytes Soluble Factors Mediating Innate Immune Responses to HIVInfection 105

Figure 1: Corresponding cyclic variation in blood cells, α₁PI, and viral load in patients treated with α₁PI augmentation.

Patients PI_zz-1 and PI_zz-2 increased from 743 to 954 and from 899 to 1024 cells∕μl, respectively. Patient Beta, who had never exhibited CD4⁺ lymphocytes in the normal range in more than 20 years, even continued to exhibit the normal range of CD4⁺ lymphocytes 2 wks after treatment stopped with 382 cells∕μl. Using regression analysis, this duration of benefit was attributed to α₁PI therapy (Fig. 2). Patient Alpha who was first infected 5 years prior to the study had not exhibited CD4⁺ lymphocytes within the normal range in 2 years. At 5 wks and 14 wks after treatment stopped, patient Alpha continued to be in the normal range with 470 cells∕μl. By regression analysis, this duration of benefit appeared to be related to antiretroviral medication as well as α₁PI therapy (Fig.

Figure 2: Duration of increase in CD4⁺ lymphocytes following α₁PI therapy. Comparison of the change in CD4⁺ lymphocytes represented in Fig. 1 before (∙), during (■), and after (W) α₁PI augmentation therapy demonstrates that the duration of benefit is 1 or 2 weeks post-treatment (Patient Beta), but not 5 or 14 weeks post-treatment (Patient Alpha). Linear regression of CD4⁺ lymphocyte changes before (solid line) and during (dashed line) show significant improvement.

CD4⁺ Lymphocyte Cycling is Sinusoidal. All Patients Exhibited Cyclic Changes in CD4⁺ Lymphocytes (Fig. 3).

Patients Alpha, Beta, and PI_zz-1 exhibited sinusoidal changes in CD4⁺ lymphocytes with periodicity 23±3.5 days (Fig. 3). Patient Gamma exhibited sinusoidal changes in CD4⁺ lymphocytes with periodicity of 15 days. Of important note, patient PI_zz-1, but none of the HIV-1 patients, exhibited sinusoidal changes in CD8⁺ lymphocytes. In patient Alpha, the sinusoidal wave was damped exhibiting decreased amplitude. In patients Beta and Gamma, the oscillations sloped downward. The 5 week treatment period for patient PIzz-2 was insufficient for determining the occurrence of periodicity. The CD4∕CD8 ratio in patients Alpha, Beta, and PIzz-1 increased following α1PI therapy at a rate of 0.02±0.008 per week (Figs. 1 and 3). The degree of increase in the CD4+ lymphocyte axis of oscillation in patients Alpha, Beta, Gamma, and PI_zz-1 was inversely related to baseline CD8+ lymphocyte percentage (n=4, r²=0.99, pand PI_zz-1 (d) over the course of Zemaira® therapy.

Acknowldegements

We wish to thank CSL Behring for contributing Zemaira®; BioReferences Laboratories for performing routine patient analyses; M.A. Reeves for data analysis; P Quartararo and Dr. M. Murtiashaw for manuscript advice; the many volunteers and patients who participated by contributing their time and blood for this study; the InfusionZTransfusion Unit nurses and Drs. A. Distenfeld, E. Medina, and M. LaBrunda for assisting with patient follow-up. This study was supported by the Harry Winston Research Foundation.

author information

V.R. is Senior Vice President of Research and Development, CSL Behring. All other authors declare no competing financial interest.

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