Factors affecting success of thymus transplantation for complete DiGeorge anomaly

Abstract

Thymus transplantation shows promise for the treatment of athymia in complete DiGeorge anomaly. This report reviews the effects of dose of thymus tissue, ABO compatibility, HLA matching, culture conditions, age of donor and immunosuppression of recipient on immune outcomes at 1 year after transplantation. Forty-nine athymic subjects have been treated with cultured postnatal allogeneic thymus tissue; 36 (73%) survive with only one subject on immunosuppression at 1.5 years. Of 31 surviving subjects more than 1 year after transplantation, 30 (97%) developed naive T cells, T-cell proliferative responses to mitogens and a diverse T-cell receptor beta variable (TCRBV) repertoire. The dose of thymus tissue, HLA matching and use of immunosuppression had nonsignificant effects on these outcome variables. Removal of deoxyguanosine from culture medium and length of culture did not adversely affect outcomes. Use of thymus tissue from donors over 1 month of age, versus under 1 month, resulted in higher total T-cell numbers (p = 0.03). However, this finding must be confirmed in a prospective trial. Although subtle immune effects may yet be associated with some of the factors tested, it is remarkable that consistently good immune outcomes result despite variation in dose, HLA matching and use of immunosuppression.

Conflict of interest statement

The authors have no conflicting financial interests.

Figures

Figure 1

Dose of thymus tissue given to 30 consecutive subjects with complete DiGeorge anomaly.

Figure 2

Lack of effect of dose on immune outcomes. A) Dose plotted versus the CD4 count at 1 year. B) The effect of dose on naïve CD4 cells at one year. C) The effect of dose on the statistical measure of TCRBV diversity, DKL, at one year. D) The effect of dose on the PHA response at one year. Trend lines and the Pearson correlation coefficients, R, are shown in each panel. The p values for these correlations were all ≥ 0.5. See Methods for explanation of subject numbers.

Figure 3

Effect of ABO compatibility of thymus graft and recipient pairs on T cell numbers at 1 and 2 years after transplantation. The “compatible” pairs included transplantation of blood group O thymuses into O (n=13), A (n=5) or B (n=2) subjects; A thymuses into A subjects (n=4); and B thymuses into B subjects (n=1). The “not compatible” pairs included transplantation of blood group A thymus into O subjects (n=4) or B thymuses into O subjects (n=2). Panels A and B thus show T cell numbers at one year in 25 subjects who received compatible thymus grafts and in 6 subjects who received incompatible grafts. Panels C and D show T cell numbers at 2 years in 20 subjects with compatible thymuses and 4 subjects with incompatible grafts. The horizontal lines indicate the mean of each group. In panel A, the mean CD4 counts were 610/mm3 and 396/mm3 for compatible and non-compatible pairs, respectively. In panel C, the mean CD4 counts were 690/mm3 and 422/mm3, respectively.

Figure 4

Effect of HLA matching on thymus transplantation. The effect of matching for 0 or 1 HLA-DR alleles between recipient and thymus tissue was assessed examining A) the CD4 number at 1 year and B) the naïve CD4 number at 1 year. The mean CD4 T cell numbers were 605/mm3 without and 500/mm3 with HLA-DR matching. The mean naïve CD4 T cell numbers were 346/mm3 without and 318/mm3 with HLA-DR matching. The effect of matching for 0 or 1-2 HLA-A or HLA-B alleles was assessed examining C) the CD8 count and D) the naïve CD8 count at one year. The mean CD8 T cell numbers were 160/mm3 without matching and 183/mm3 with matching. The mean naïve CD8 numbers were 86/mm3 without matching and 127/mm3 with matching. In all cases the p value reflects the comparison of counts with no matching versus counts with 1 or more alleles matching. See Methods for explanation of subject numbers.

Figure 5

The effect of donor factors on later CD4+ T cell development. The effect of A) conotruncal heart defects and B) age under 1 month on effectiveness of thymus later use for transplantation. In A, the mean CD4 counts are 652/mm3 with conotruncal donor vs. 539/mm3 without conotruncal donor. In B, the mean CD4 counts were 689/mm3 if the donor was > 1 month compared to 511/mm3 when the donor was < 1 month.

Figure 6

Culture conditions and immune outcomes at one year. The effect of A) length of time in culture and B) length of time in culture with deoxyguanosine on the CD4 count at one year. The effect of time in deoxyguanosine also on C) the number of naïve CD4 T cells at one year and D) the T cell receptor diversity assessed by the CD4 DKL score at one year. See Methods for explanation of subject numbers.