| Abstract|| |
Mismatching for HLA antigens in renal transplant recipients effects the graft survival and may also be responsible for the development of malignancy including skin cancer due to the intensive immunosuppression, continuous antigenic stimulation or both. In this article, available data are reviewed and an attempt is made to show that some specific immunologic and immuno-genetic factors like the HLA system also play a role in the development of skin cancer in renal transplant recipients.
Keywords: Renal transplant, HLA, Skin cancer.
|How to cite this article:|
Qureshi B H. Skin Cancer and HLA Association in Renal Transplant Recipients. Saudi J Kidney Dis Transpl 1996;7:394-7
| Introduction|| |
Immune surveillance is the mechanism by which somatic tissues are protected from getting transformed to malignant tissues. Tlymphocytes and natural killer cells constitute the major components of immune surveillance  . In order to trigger an immune response against any viral or tumor antigens, the recognition by T-lymphocytes through the HLA system is required. The two types of HLA molecules, namely class I and class II antigens, are present on CD8+ and CD4+ T-cells respectively. Thus, the CD4 + T-Lymphocytes recognize the foreign peptide in the context of class II HLA antigens while the CD8 + lymphocytes do the same in the context of HLA class I molecule , .
Renal transplant recipients are known to be at an increased risk for developing both warts and skin cancer. Besides the immunosuppression, solar radiation and viral warts are believed to be important risk factors in the development of skin cancer in such patients , . Thus, the human papilloma viruses (HPV), especially, Epidermodysplasia verruciformis (EV)-associated HPV- 5, 8, 17, 20 and 47, are thought to play a role in the pathogenesis of skin cancers in renal transplant recipients , . Another interesting observation is that the risk of skin cancer in these patients is higher than in patients treated with immunosuppressive drugs for other reasons  . This increased risk may be due to the effect of intensive immunosuppression, continuous exposure to allo-anti-gens or both.
Additionally, other specific immunologic and immuno-genetic factors may also play a role  . Also, the nonspecific immune surveillance against skin cancer is hampered in transplant recipients because of a depressed natural killer cell function  .
| Skin Cancer and HLA Association|| |
Several reports have been published from various centers showing the association of both class I and class II antigens in the development of skin cancer. For example, HLA A3 was found in increasing frequency in patients with squamous cell carcinoma in a study from the Netherlands; however, this was not confirmed in other studies , [Table - 1]. Similar association of risk of skin cancer in transplant recipients with HLA B27 has been described [Table - 2], , . These observations suggest that increased susceptibility to skin cancer is associated with class I antigens. Czarnecki and coworkers reported that the occurrence of skin cancer is associated with the class II antigens as well (e.g., HLA DR7) , [Table - 3]. Another interesting observation has been the negative association between HLA All and skin cancer as has been reported from some centers ,,,,, [Table - 4].
HLA matching plays an important role in graft survival , . Long-term antigenic stimulation by a poorly matched graft is thought to induce skin cancer, due either to a direct effect on the immune repertoire, or indirectly by necessitating a higher dose of immuno-suppressive therapy  . It has been found that matching for B and DR locus antigens is more important for better graft survival than the A locus antigens , . This may indicate that B and DR antigens are more immunogenic. Moreover, the number of cytotoxic T-cell precursors in the peripheral blood specific for HLA-B mismatches is much higher than those against HLA-A  . Therefore, if an effect of HLA class matching on the occurrence of skin cancer exists, an HLA-B effect would be expected, as tolerance for HLA-B has more implications on the immune response than tolerance for HLA-A. In fact, HLA-B mismatching has been shown to be associated with a much higher risk of squamous cell carcinoma in renal transplant recipients. The relative risk of squamous cell carcinoma was 2.6 and 5.00 with mismatching for one and two HLA-B antigens respectively, as compared with no mismatches. In these cases, the occurrence of skin cancer was not related to the number of rejection episodes or cumulative doses of immuno-suppressive drugs  .
The association of skin cancer with certain HLA class I molecules suggests an impairment of the immune response in the effector phase. The structure of the class I antigen is important to facilitate the recognition of viral and tumor antigens by CD8 + cytotoxic T-cells. For example, the discriminating site of HLA Al, A3 and All is located at codon 9 of the a domain, a critical site in the floor of the antigen-binding groove which is important for the recognition of peptides  . In the HLA Al and A3 antigens, codon 9 codes for phenylalanine and in HLA All, it codes for tyrosine, two amino acids that differ only in one hydroxy group. This difference may be responsible for the protective effect observed in renal transplant recipients with HLA All and this can be attributed to the effective presentation of antigens of squamous cell carcinoma and HPV to the cytoxic T-cells.
In contrast, HLA B 27 may not be very efficient in presenting peptides derived from early transforming proteins of HPV to cytoxic T cells. In-vitro studies on the antigen presenting capacity of HLA All, regarding peptides derived from HPV and squamous cell carcinoma, are in progress to establish the relationship between HLA All and protection against skin cancer more definitely.
The association of skin cancer with class II antigens, e.g., HLA DR-7, suggests an impaired response of CD4+ T-cells with HLA class II associated peptide  . Renal transplant recipients who were found defective in class switch from IgM to IgG, concerning the antibody production to the antigens encoded by the late antigen Li of HPV 8, are at an increased risk of skin cancer  . A strong linkage between the lack of a class switch of antibody production in response to Li of HPV8 and HLA DR7 was observed, which lends further support to the association of skin cancer with HLA DR7.
Thus, it seems that transplant recipients with HLA A3, B27 and DR7 and mismatching at certain HLA loci are more susceptible to skin cancer while HLA All has a protective effect. Also, there seems to be a genetic control involving the HLA system on the development of, and protection against, skin cancer in renal transplant recipients. More studies are needed to validate this hypothesis.
| References|| |
|1.||Streilein JW. Immunogenetic factors in skincancer. N Engl J Med 1991;325:884-7. [PUBMED] |
|2.||Monaco JJ. A molecular model of MHC class Irestricted antigen processing. Immunol Today 1992;13:173-9. [PUBMED] |
|3.||Neefjes JJ, Ploegh HL. Intracellular transport of MHC class II molecules. Immunol Today1992;13:179-84. [PUBMED] |
|4.||Boyle J, Mackie RM, Briggs JD, Junor BJ, Aitchison TC. Cancer, warts, and sunshine in renal transplant patients. A case-control study. Lancet 1984;l:702-5. |
|5.||Tieben LM, Berkhout RJ, Smits HL, et al. Detection of epidermodysplasia verruciformis-like human palilloma virus types in malignant and premalignant skin lesions of renal transplant recipients. Br J Dermatol 1994;131:226-30. [PUBMED] |
|6.||Bavinck JN, Gissmann L, Claas FH, et al. Relation between skin cancer, humoral responses to human papilloma viruses and HLA class II molecules in renal transplant recipients. J Immu nol 1993;151:1579-86. |
|7.||Kinlen LJ. Incidence of cancer in rheumatoidarthritis and other disorders after immunosuppressive treatment. Am J Med 1985;78:44-9. |
|8.||Bavinck JN, Vermeer BJ, van der Woude FJ, et al. Relation between skin cancer and HLA antigens in renal transplant recipients. N Engl J Med1990;325:843. |
|9.||Legendre CM, Guttmann RD, Yip GH. Natural killer cell subsets in long-term renal allograft recipients. A phenotypic and functional study. Transplantation 1986;42:347-52. |
|10.||Bouwes Bavinck JN, Kootte AM, Van Der Woude FJ, Vandenbroucke JP, Vermeer BJ, Claas FH. Ona possible protective effect of HLA-A11 againstskin cancer and keratotic skin lesions in renal transplant recipients. J Invest Dermatol 1991;97:269-72. [PUBMED] |
|11.||Glover MT, Bodmer J, Kennedy LJ, et al. HLA antigen frequencies in renal transplant recipients and nonimmunosuppressed patients with non melanoma skin cancer. Eur J Cancer1993;29A(4):520-4. |
|12.||Bavinck JN, Kootte AM, van der Woude FJ, Vanden broucke JP, Vermeer BJ, Claas FH.HLA-A11 associated resistance to skin cancer in renal transplant patients. N Engl J Med1990;323:1350. |
|13.||Czarnecki D, Zalcberg J, Nicholson I, Tait B. Skin cancer and HLA antigens. N Engl J Med1992;326:765-6. [PUBMED] |
|14.||Czarnecki D, Watkins F, Leahy S, et al. Skin cancers and HLA frequencies in renal transplant recipients. Dermatology 1992;185:9-11. [PUBMED] |
|15.||McGregor JM, Reddi G, MacDonald D, Vaughan RW, Welsh KI. HLA-A11 in renal allograft recipients with skin cancer. J Invest Dermatol 1992;98:261-2. [PUBMED] |
|16.||Thorogood J, Persijn GG, Schreuder GM, et al.The effect of HLA matching on kidney graft survival in separate post transplantation intervals. Transplantation 1990;50:146-50. [PUBMED] |
|17.||Van Rood JJ, Hendriks GF, D' Amaro J, et al.HLA matching patient survival and immune response genes in renal transplantation. Transplant Proc 1985;17:681. |
|18.||Zhang L, van Bree S, van Rood JJ, Claas FH. The effect of individual HLA-A and B mismatches on the generation of cytotoxic T lymphocyte precursors. Transplantation 1990;50:1008-10. [PUBMED] |
|19.||Pharham P, Lomen VE, Lawler DA, et al. Nature of polymorphism in HLAA,B, and C molecules. |
B H Qureshi
Laboratory and Transfusion Services, King Saud Hospital, P.O. Box 981, Unayzah, Al-Qassim
[Table - 1], [Table - 2], [Table - 3], [Table - 4]