The reconstitution of the thymus in immunosuppressed individuals restores CD4-specific cellular and humoral immune responses

Abstract

Infection with HIV-1 frequently results in the loss of specific cellular immune responses and an associated lack of antibodies. Recombinant growth hormone (rGH) administration reconstitutes thymic tissue and boosts the levels of peripheral T cells, so rGH therapy may be an effective adjuvant through promoting the recovery of lost cellular and T-cell-dependent humoral immune responses in immunosuppressed individuals. To test this concept, we administered rGH to a clinically defined group of HIV-1-infected subjects with defective cellular and serological immune responses to at least one of three commonly employed vaccines (hepatitis A, hepatitis B or tetanus toxoid). Of the original 278 HIV-1-infected patients entering the trial, only 20 conformed to these immunological criteria and were randomized into three groups: Group A (n = 8) receiving rGH and challenged with the same vaccine to which they were unresponsive and Groups B (n = 5) and C (n = 7) who received either rGH or vaccination alone, respectively. Of the eight subjects in Group A, five recovered CD4 cellular responses to vaccine antigen and four of these produced the corresponding antibodies. In the controls, three of the five in group B recovered cellular responses with two producing antibodies, whereas three of the seven in Group C recovered CD4 responses, with only two producing antibodies. Significantly, whereas seven of ten patients receiving rGH treatment in Group A (six patients) and B (one patient) recovered T-cell responses to HIVp24, only two of six in Group C responded similarly. In conclusion, reconstitution of the thymus in immunosuppressed adults through rGH hormone treatment restored both specific antibody and CD4 T-cell responses.

Figure 1

Study design. I/E* inclusion/exclusion crtieria; ** haematological, biochemical, virological and immunological assays and clinical examiniation; CAT, computed axial tomography of the thyroid.

Figure 2

Patients chart flow.

Figure 3

Effect of growth hormone therapy on the reconstitution of the thymus. Changes in thymic volume (cm³) at months 6 and 12 compared with baseline levels. Mean changes in the thymic volume of 12 HIV-1-infected patients who received recombinant growth hormone (Groups A + B) versus that of the seven control patients (Group C). The thymic tissue receded after GH treatment was stopped, but it remained larger than the pre-treatment size (a). Comparison of T-cell receptor excision cycles (TREC) in patients who received the recombinant growth hormone (Groups A + B; n = 12) compared with those who had only received vaccination (Group C; n = 7, and Group D; n = 7) at 6 and 12 months after the initiation of the trial. The results are expressed as copies of TRECs/10⁶ cells (b).The absolute numbers of CD4⁺ CD45⁺ CD31⁺ recent thymic emigrants measured at baseline and during the next 12 months. Broken line: patients who received growth hormone. Continuous line: control group. There was a statistically significant difference between the two groups (P < 0·01) (c). A statistically significant correlation between the levels of TREC and the absolute numbers of CD4⁺ CD45RA⁺ CD31⁺ T cells (d).

Figure 4

Effect of growth hormone treatment on the CD4 and CD8 subsets. The absolute numbers of CD4 (a) and CD8 (b) levels and the percentages of the CD4 and CD8 subsets were measured at months 0 (baseline), 2, 4, 5, 6, 9 and 12, as described in the Materials and methods. From the 20 HIV-1-positive individuals included in the trial, 13 were treated with recombinant growth hormone (rGH) for 6 months (indicated by grey shading). The mean and the standard error of the absolute CD4 (a) and CD8 (b) T-cell values from patients who received rGH (continuous line) (Groups A and B) and those who did not (discontinuous line, Group C). (c) to (f) show the percentages of CD4 and CD8 subpopulations from patients who received growth hormone (Group A and B; c, d) and those who did not (Group C; e, f).